Exploring the Role of Neuroplasticity - Neurociência (2025)

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<p>Citation: Marzola, P.; Melzer, T.;</p><p>Pavesi, E.; Gil-Mohapel, J.; Brocardo,</p><p>P.S. Exploring the Role of</p><p>Neuroplasticity in Development,</p><p>Aging, and Neurodegeneration. Brain</p><p>Sci. 2023, 13, 1610. https://doi.org/</p><p>10.3390/brainsci13121610</p><p>Academic Editor: Mahesh</p><p>Kandasamy</p><p>Received: 23 October 2023</p><p>Revised: 16 November 2023</p><p>Accepted: 18 November 2023</p><p>Published: 21 November 2023</p><p>Copyright: © 2023 by the authors.</p><p>Licensee MDPI, Basel, Switzerland.</p><p>This article is an open access article</p><p>distributed under the terms and</p><p>conditions of the Creative Commons</p><p>Attribution (CC BY) license (https://</p><p>creativecommons.org/licenses/by/</p><p>4.0/).</p><p>brain</p><p>sciences</p><p>Review</p><p>Exploring the Role of Neuroplasticity in Development, Aging,</p><p>and Neurodegeneration</p><p>Patrícia Marzola 1 , Thayza Melzer 1, Eloisa Pavesi 1 , Joana Gil-Mohapel 2,3,* and Patricia S. Brocardo 1,*</p><p>1 Department of Morphological Sciences and Graduate Neuroscience Program, Center of Biological Sciences,</p><p>Federal University of Santa Catarina, Florianopolis 88040-900, SC, Brazil; patriciarmarzola@gmail.com (P.M.);</p><p>melzer.th@gmail.com (T.M.); eloisapavesi@gmail.com (E.P.)</p><p>2 Division of Medical Sciences, University of Victoria, Victoria, BC V8P 5C2, Canada</p><p>3 Island Medical Program, Faculty of Medicine, University of British Columbia, Victoria, BC V8P 5C2, Canada</p><p>* Correspondence: jgil@uvic.ca (J.G.-M.); patricia.brocardo@ufsc.br (P.S.B.)</p><p>Abstract: Neuroplasticity refers to the ability of the brain to reorganize and modify its neural con-</p><p>nections in response to environmental stimuli, experience, learning, injury, and disease processes. It</p><p>encompasses a range of mechanisms, including changes in synaptic strength and connectivity, the</p><p>formation of new synapses, alterations in the structure and function of neurons, and the generation</p><p>of new neurons. Neuroplasticity plays a crucial role in developing and maintaining brain function,</p><p>including learning and memory, as well as in recovery from brain injury and adaptation to environ-</p><p>mental changes. In this review, we explore the vast potential of neuroplasticity in various aspects of</p><p>brain function across the lifespan and in the context of disease. Changes in the aging brain and the</p><p>significance of neuroplasticity in maintaining cognitive function later in life will also be reviewed. Fi-</p><p>nally, we will discuss common mechanisms associated with age-related neurodegenerative processes</p><p>(including protein aggregation and accumulation, mitochondrial dysfunction, oxidative stress, and</p><p>neuroinflammation) and how these processes can be mitigated, at least partially, by non-invasive and</p><p>non-pharmacologic lifestyle interventions aimed at promoting and harnessing neuroplasticity.</p><p>Keywords: aging; cognitive function; lifestyle interventions; neurodegeneration; neurodevelopment;</p><p>neuroplasticity</p><p>1. Introduction</p><p>The concept of neuroplasticity was first introduced by William James in 1890, and a few</p><p>decades later, Jerzy Konorski coined the term “neural plasticity” [1,2]. Neuroplasticity refers</p><p>to changes in brain structure and function throughout the lifespan. Neuroplasticity enables</p><p>the brain to change and adapt to intrinsic or extrinsic stimuli by reorganizing its structure,</p><p>function, or connections, resulting in physiological and morphological modifications. This</p><p>dynamic process allows us to adjust to different experiences and circumstances and plays a</p><p>significant role in learning, memory, and recovery from brain injuries [3].</p><p>Due to the multifaceted nature of neuroplasticity, different types of plasticity can</p><p>impact brain structure and function [4,5]. Structural neuroplasticity refers to changes in the</p><p>physical structures of neurons and neural networks, including the number, shape, strength,</p><p>and connectivity of synapses [6], thus enabling the brain to adapt to changing environments</p><p>and experiences. Numerous studies have indicated that structural plasticity occurs during</p><p>development and continues into adulthood [7–9]. On the other hand, functional neuro-</p><p>plasticity refers to changes in neural network properties that involve efficiency, strength,</p><p>and synchrony changes of synapses. Functional plasticity occurs rapidly, affecting various</p><p>cognitive and behavioral processes relating to attention, memory, and perception [5,10].</p><p>One well-studied example of structural neuroplasticity is adult neurogenesis, the pro-</p><p>cess by which new neurons are generated in the adult brain. This process occurs primarily</p><p>in the subventricular zone (SVZ) that lines the lateral ventricles and in the dentate gyrus</p><p>Brain Sci. 2023, 13, 1610. https://doi.org/10.3390/brainsci13121610 https://www.mdpi.com/journal/brainsci</p><p>https://doi.org/10.3390/brainsci13121610</p><p>https://doi.org/10.3390/brainsci13121610</p><p>https://creativecommons.org/</p><p>https://creativecommons.org/licenses/by/4.0/</p><p>https://creativecommons.org/licenses/by/4.0/</p><p>https://www.mdpi.com/journal/brainsci</p><p>https://www.mdpi.com</p><p>https://orcid.org/0000-0001-8152-5674</p><p>https://orcid.org/0000-0003-0428-6694</p><p>https://orcid.org/0000-0003-4982-1662</p><p>https://doi.org/10.3390/brainsci13121610</p><p>https://www.mdpi.com/journal/brainsci</p><p>https://www.mdpi.com/article/10.3390/brainsci13121610?type=check_update&version=1</p><p>Brain Sci. 2023, 13, 1610 2 of 32</p><p>of the hippocampus, a brain region essential for learning and memory [9,11–13]. Several</p><p>studies have shown that increased physical activity, exposure to enriched environments,</p><p>and certain drugs can enhance neurogenesis and improve learning and memory [8,14–16].</p><p>Another example of structural neuroplasticity is dendritic spine remodeling, the process</p><p>by which dendritic spines change in size, shape, and number in response to experience.</p><p>Animal studies have shown that dendritic spine remodeling also plays a crucial role in</p><p>learning and memory [17,18].</p><p>Functional neuroplasticity is thought to underlie memory formation, skill acquisition,</p><p>and recovery from injury. An example of functional neuroplasticity is long-term potentia-</p><p>tion (LTP), the persistent strengthening of synapses in response to repeated stimulation.</p><p>LTP is thought to be a key mechanism underlying learning and memory [19]. Conversely,</p><p>long-term depression (LTD) is the persistent weakening of synapses and also plays a role</p><p>in learning and memory [20,21]. Another example of functional neuroplasticity is cortical</p><p>reorganization, the process by which the brain’s sensory maps can change in response to</p><p>experience or injury. Learning new abilities results in changes to functional connectivity</p><p>among brain areas involved with motor control, sensory processing, and attention. For</p><p>example, blind individuals can have enhanced sensory processing in other modalities, such</p><p>as touch and hearing, due to cortical reorganization [22].</p><p>In the perinatal and early childhood periods, the brain undergoes rapid and extensive</p><p>growth and development, during which plasticity is particularly high. Studies have</p><p>shown that this period is characterized by a heightened sensitivity to environmental input,</p><p>which facilitates the formation of new neural connections [23]. In contrast, plasticity in</p><p>later stages of the lifespan is more tightly regulated and context-dependent. Changes in</p><p>neural activity, environmental factors, and behavioral outcomes can trigger the release of</p><p>specific neurotransmitters, enabling changes in neural connections only under contextual</p><p>conditions that facilitate plasticity [24]. Moreover, recent studies have suggested that the</p><p>regulation of plasticity in the mature brain occurs as a continuum, with different levels of</p><p>plasticity occurring under different conditions [25]. These findings suggest that plasticity</p><p>is a dynamic process that can be modulated and affected by various factors, including</p><p>age, experience, and environmental conditions. Understanding these factors can aid in</p><p>developing effective strategies to harness the power of neuroplasticity and minimize its</p><p>negative effects, leading to better treatments and outcomes for various neurological and</p><p>neurodegenerative conditions.</p><p>2. Neuroplasticity</p><p>Neuroplasticity,</p><p>adults [321], and promoted cognitive function</p><p>in individuals with mild cognitive impairment and dementia [322–324]. A systematic re-</p><p>view and meta-analysis of 17 randomized controlled trials found that exercise interventions</p><p>improved cognitive function, including memory, attention, processing speed, and executive</p><p>function, in older adults [325]. A separate meta-analysis of 29 randomized controlled trials</p><p>also found that exercise interventions were associated with significant improvements in</p><p>cognitive function in healthy older adults [326]. A recent study using transcranial mag-</p><p>netic stimulation (TMS) found that older adults who engaged in regular physical exercise</p><p>had more remarkable cortical plasticity than those who did not exercise regularly [327].</p><p>This suggests that exercise directly impacts the ability of the brain to adapt and change</p><p>in response to environmental stimuli during aging. In addition, a study using magnetic</p><p>resonance imaging (MRI) found that older adults who engaged in regular physical activity</p><p>had greater gray matter volume in the prefrontal cortex, a brain region important for</p><p>higher-order cognitive functions and decision making [328].</p><p>Together, these studies suggest that exercise can be a powerful tool for promoting</p><p>neuroplasticity and cognitive health during aging. By increasing trophic support through</p><p>the production of BDNF and promoting changes in brain structure and function, exercise</p><p>may help protect the brain against age-related cognitive decline and improve the quality of</p><p>life in later years.</p><p>4.4.2. Cognitive Stimulation and Socialization</p><p>Several lines of evidence have suggested that cognitive stimulation can effectively</p><p>promote neuroplasticity and brain health during aging. Cognitive stimulation encompasses</p><p>activities that challenge the brain, such as reading, writing, playing cognitive games, or</p><p>learning new skills. These activities promote the formation of new neuronal connections</p><p>and can help maintain cognitive function during aging [329]. A systematic review and meta-</p><p>analysis found that engaging in mentally stimulating activities was associated with a lower</p><p>risk of cognitive decline and dementia [330]. Older adults engaged in mentally stimulating</p><p>activities had greater gray matter volume in brain regions important for memory and</p><p>cognitive function [331], and an active cognitive lifestyle is associated with a more favorable</p><p>cognitive trajectory in older persons [332]. Leisure activities such as reading, playing board</p><p>games, playing musical instruments, and dancing were associated with a reduced risk of</p><p>dementia in individuals older than 75 [333]. Learning new skills is one way to engage in</p><p>mentally stimulating activities. In fact, learning a new skill, such as juggling, was associated</p><p>with changes in brain structure and function, including increased gray matter volume in</p><p>the visual and motor areas of the brain [81,82].</p><p>Socially interacting with others, such as friends and family, and engaging in social</p><p>activities can also promote cognitive and emotional stimulation. Older adults who engaged</p><p>in social activities, such as volunteering or participating in community events, had a lower</p><p>risk of cognitive decline than those who did not engage in such activities [334]. On the other</p><p>hand, a study found that social isolation was associated with a higher risk of dementia in</p><p>older adults. This study followed over 2000 older adults for up to 7 years and found that</p><p>those who were socially isolated had a 60% higher risk of developing dementia than those</p><p>with social support [335]. Of note, socialization has been shown to promote the formation</p><p>of new neuronal connections and enhance cognitive function. Indeed, socializing with</p><p>Brain Sci. 2023, 13, 1610 18 of 32</p><p>others was associated with increased gray matter volume in brain regions important for</p><p>memory and social cognition [336].</p><p>Furthermore, several studies showed that genetic and lifestyle factors play a role in</p><p>determining the individual risk of dementia and cognitive impairment. The ε4 allele of the</p><p>apolipoprotein E (APOE ε4) gene is the strongest known genetic risk factor for dementia</p><p>and cognitive impairment. The association between APOE ε4 and faster cognitive decline</p><p>was reduced in participants who were regularly engaged in productive activities [337].</p><p>4.4.3. Diet and Caloric Restriction</p><p>Diet plays a significant role in promoting neuroplasticity, especially during the aging</p><p>process. The brain is a complex organ that requires numerous nutrients, including vitamins,</p><p>minerals, antioxidants, and essential fatty acids [338]. Several studies have found that a</p><p>healthy diet rich in fruits, vegetables, whole grains, and lean protein provides the nutrients</p><p>necessary for optimal brain function [339,340].</p><p>In particular, the role of omega-3 fatty acids in promoting neuroplasticity is well</p><p>documented. These fatty acids are essential for brain health and are found in high con-</p><p>centrations in fatty fish such as salmon, sardines, and mackerel [341]. For example, a</p><p>randomized controlled trial involving older adults with mild cognitive impairment found</p><p>that supplementation with omega-3 fatty acids for 12 weeks significantly improved cogni-</p><p>tive function compared to the placebo group [342]. In a different study, supplementation</p><p>with omega-3 fatty acids was also shown to improve cognitive function in healthy older</p><p>adults [343]. Furthermore, Dullemeijer et al. (2007) found that higher plasma levels of n-3</p><p>polyunsaturated fatty acids were associated with a reduced decline in sensorimotor speed</p><p>and complex cognitive processing in older adults [344]. In addition to omega-3 fatty acids,</p><p>macro and micronutrients present in balanced diets, such as B vitamins and flavonoids,</p><p>can prevent or mitigate age-related degenerative processes [345].</p><p>Conversely, diets high in saturated and trans fats have been linked to cognitive</p><p>decline and dementia. A systematic review and meta-analysis of prospective studies</p><p>found that a higher intake of saturated fats was associated with a higher risk of cognitive</p><p>impairment and dementia [346]. Similarly, a study by Morris et al. found that a diet high</p><p>in saturated fat was associated with a greater risk of developing AD [347]. In agreement,</p><p>Solfrizzi et al. (2006) found that a diet high in trans fats was associated with cognitive</p><p>decline in older adults [348]. Of note, trans fats have been shown to have adverse effects on</p><p>brain function, as they can impair synaptic plasticity, alter membrane composition, and</p><p>increase neuroinflammation [346]. These findings suggest that diets high in saturated and</p><p>trans fats may negatively impact brain health and should be avoided.</p><p>Caloric restriction is another dietary strategy that promotes neuroplasticity and im-</p><p>proves cognitive function. Caloric restriction involves reducing calorie intake by a certain</p><p>percentage while maintaining adequate nutrition [349]. Animal studies have demonstrated</p><p>that caloric restriction can enhance neuroplasticity by increasing the production of neu-</p><p>rotrophic factors, such as BDNF [350,351]. Recent human studies have also suggested that</p><p>caloric restriction may benefit brain function. A randomized controlled trial of overweight</p><p>adults found that a 25% reduction in calorie intake for two years resulted in significant im-</p><p>provements in verbal memory and executive function compared to the control group [352].</p><p>4.4.4. Sleep Hygiene and Quality of Sleep</p><p>Sleep is critical in maintaining brain health and cognitive function, particularly in older</p><p>adults. Numerous studies have demonstrated the importance of sleep in promoting neuro-</p><p>plasticity, particularly during learning and memory consolidation [353,354]. Sleep is also</p><p>essential for clearing out toxic waste products and allowing the brain to regenerate [355].</p><p>Sleep deprivation has been associated with cognitive decline, particularly in older</p><p>adults. Indeed, chronic sleep deprivation has been linked to a faster rate of cognitive</p><p>decline in this population [356], while poor sleep quality was associated</p><p>with a greater</p><p>risk of developing dementia [357]. Recently, a study by Lucey and colleagues (2021) found</p><p>Brain Sci. 2023, 13, 1610 19 of 32</p><p>that disrupted sleep was associated with increased levels of AD-related proteins in the</p><p>cerebrospinal fluid [358].</p><p>Given this, and to promote optimal brain function, it is recommended that older</p><p>adults sleep 7–8 h per night [359]. Also, maintaining good sleep hygiene practices, such</p><p>as avoiding caffeine and electronic devices before bedtime and creating a relaxing sleep</p><p>environment, can help improve the quality and quantity of sleep. Several lines of evidence</p><p>have also highlighted the importance of regular exercise, healthy eating, and managing</p><p>stress for promoting good sleep and overall brain health [360,361].</p><p>5. Conclusions</p><p>Neurodevelopmental exposures, numerous lifestyle factors, acute neurological pro-</p><p>cesses (such as stroke and TBI), and neurodegenerative processes (such as AD and PD)</p><p>can all disrupt neuroplasticity, leading to impairments in motor skills, affective behaviors,</p><p>and cognitive function. Nevertheless, recent studies have highlighted the brain’s ability</p><p>to compensate for these impairments through processes involving neural reorganization,</p><p>which consists of recruiting other brain regions and neuronal circuits to compensate for the</p><p>damaged ones [362]. Psychological traits, such as personality, motivation, and attention,</p><p>also play a significant role in neuroplasticity mechanisms. For instance, individuals with</p><p>high levels of motivation have been shown to exhibit greater neuroplasticity than those</p><p>with low levels of motivation [363].</p><p>Understanding individual differences in experience-dependent neuroplasticity mecha-</p><p>nisms is critical for developing personalized approaches to improving cognitive function</p><p>and promoting recovery from brain injury or disease. In addition, promoting healthy</p><p>lifestyles, including physical exercise, cognitive and social stimulation, a healthy and bal-</p><p>anced diet, and good sleep hygiene, can go a long way in preventing or halting many</p><p>age-related conditions and promoting overall brain health. By promoting healthy lifestyles</p><p>and optimizing personalized treatment options that regulate and promote neuroplasticity,</p><p>we can effectively harness the power of brain plasticity.</p><p>Author Contributions: P.M., T.M. and E.P.: writing of original manuscript draft. J.G.-M.: funding</p><p>acquisition, conceptualization, review and editing of the final manuscript draft. P.S.B.: funding</p><p>acquisition, conceptualization, supervision, review and editing of the manuscript. All authors have</p><p>read and agreed to the published version of the manuscript.</p><p>Funding: This work was supported by the Fundação de Amparo à Pesquisa e Inovação do Estado de</p><p>Santa Catarina (FAPESC, Florianópolis, SC, Brazil, 2021TR1523). P.S.B. received a Conselho Nacional</p><p>de Desenvolvimento Científico e Tecnológico (CNPq; Brazil) Research Productivity Fellowship. J.G.M.</p><p>acknowledges funding from the University of Victoria (UVic, Victoria, BC, Canada) – São Paulo</p><p>Research Foundation (FAPESP, São Paulo, SP, Brazil) SPRINT partnership (UVic-FAPESP SPRINT</p><p>1/2018).</p><p>Institutional Review Board Statement: Not applicable.</p><p>Informed Consent Statement: Not applicable.</p><p>Data Availability Statement: Not applicable.</p><p>Conflicts of Interest: The authors declare no conflict of interest.</p><p>References</p><p>1. James, W. Habits. In The Principles of Psychology; Henry Holt and Company: New York, NY, USA, 1890; pp. 104–127.</p><p>2. Konorski, J. Conditioned Reflexes and Neuron Organization, Facsimile Reprint of the 1948; Cambridge University Press:</p><p>Cambridge, UK, 1968.</p><p>3. Voss, P.; Thomas, M.E.; Cisneros-Franco, J.M.; de Villers-Sidani, É. Dynamic Brains and the Changing Rules of Neuroplasticity:</p><p>Implications for Learning and Recovery. Front. Psychol. 2017, 8, 1657. [CrossRef]</p><p>4. 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[CrossRef]</p><p>https://doi.org/10.1152/advan.00088.2014</p><p>https://doi.org/10.1016/bs.pmbts.2015.08.001</p><p>https://doi.org/10.1515/REVNEURO.2010.21.3.187</p><p>https://doi.org/10.1111/j.1460-9568.2008.06310.x</p><p>https://doi.org/10.1038/nn.2349</p><p>https://doi.org/10.1016/j.biopha.2015.07.025</p><p>https://doi.org/10.1186/s40035-017-0077-5</p><p>also known as brain plasticity or neural plasticity, is the biological</p><p>capacity of the brain to adapt physiologically or even alter its anatomical structure in</p><p>response to stimuli or damage [26]. This ability is central to learning, memory, injury</p><p>recovery, and adaptation to environmental changes [27].</p><p>2.1. Structural Neuroplasticity</p><p>Structural neuroplasticity refers to physical changes to neural circuits, including the</p><p>growth of new dendritic spines, axonal sprouting, and even neurogenesis. In particular, neu-</p><p>rogenesis refers to generating new functional neurons, a multifaceted and tightly regulated</p><p>process involving the proliferation, differentiation, and integration of new neurons from</p><p>neural precursor cells. Each stage is characterized by the activation and presence of distinct</p><p>transcriptional factors and markers [12,28–30]. Structural neuroplasticity is essential to</p><p>rewiring the brain and has implications for recovery after brain injury, neurodevelopment,</p><p>and adaptations to sensory input alterations throughout life [31].</p><p>2.1.1. Developmental Neurogenesis and Synaptogenesis</p><p>The development of the central nervous system (CNS) begins in the early weeks</p><p>following fertilization, shortly after formation of the three embryonic germ layers, ectoderm,</p><p>mesoderm, and endoderm, a crucial phase during embryonic development. The CNS</p><p>Brain Sci. 2023, 13, 1610 3 of 32</p><p>derives from the differentiation of multipotent cells present in the ectoderm through the</p><p>formation of the neural plate in the dorsal region of the embryo. This neural plate will</p><p>fold its crest in the craniocaudal and rostrocaudal directions, forming the neural tube at</p><p>embryonic day 30 in the human [32]. The closure of the neural tube marks the beginning</p><p>of rapid brain enlargement from two groups of cells: neural stem cells (NSCs), which are</p><p>multipotent cells that can give rise to various types of neural cells, including neurons,</p><p>astrocytes, and oligodendrocytes, and express markers such as Sox 2 and Nestin; and</p><p>neural precursor cells (NPCs), which are immediate descendants of neural stem cells, are</p><p>committed to a neuronal fate and express markers such as Pax6, Dlx2, and Tbr2 [30,32].</p><p>Between weeks 4 and 5 of human embryonic development begins a phase known as</p><p>interkinetic nuclear migration of NSCs and NPCs, which results in the symmetric division</p><p>along the ventricular edge. This early proliferation leads to an exponential increase in the</p><p>pool of progenitor cells that contribute to the expansion of surface area and thickness of</p><p>the ventricular zone [30,33,34]. Around gestational week 5 (human embryonic day 42), the</p><p>NPCs located in the ventricular zone, referred to as radial glial cells, begin to switch from</p><p>symmetric to asymmetric cell division, generating one daughter cell that remains in the</p><p>ventricular zone as a radial glial cell and a postmitotic neuron, marking the beginning of</p><p>neurogenesis itself [33]. The process of differentiation of NPCs into neurons involves the</p><p>successive expression of specific transcription factors and proteins, including Neurogenin</p><p>(Ngn) and Mash 1 (Ascl1), doublecortin (DCX), βIII-tubulin (Tuj1), and finally NeuN,</p><p>a marker of mature neurons [34]. Of note, new neurons also need to migrate to their</p><p>appropriate locations within the brain. This process involves the support of radial glial cells</p><p>and Cajal–Retzius cells, which create pathways such as the reelin pathway to aid migrating</p><p>neurons in reaching their final destination [35].</p><p>A final step in the neurogenic process involves establishing functional connections</p><p>between the newly generated neurons to form neural circuits. This process relies on</p><p>synaptic plasticity or synaptogenesis. Synaptogenesis begins approximately in human</p><p>gestational week 27 and continues to occur after birth. During the postnatal period,</p><p>synapses are produced rapidly; by age two, the number of synapses is estimated to be</p><p>twice the number in the adult brain. Indeed, synaptogenesis is an incredibly dynamic</p><p>process in the human cerebral cortex in infancy and childhood [27], with the postnatal</p><p>period being marked by enhanced experience-dependent sensitivity to sensory information.</p><p>In addition, synaptic strength and efficacy alterations occur during the development [27],</p><p>allowing the developing brain to adapt to environmental stimuli. This “critical period” is</p><p>not sustained into adulthood, though, thus restricting the ability to indiscriminately store</p><p>new sensory information [36]. Indeed, the number of synapses falls over the subsequent</p><p>years and into adolescence through a process referred to as synaptic pruning, through</p><p>which necessary synapses are preserved and redundant ones are eliminated [37]. These</p><p>findings support the idea of “windows of opportunity” that enable the construction and</p><p>consolidation of experience-dependent structural and functional brain connections during</p><p>the neurodevelopment period [38] and explain why children can readily acquire new</p><p>languages (and other skills). At the same time, this ability requires much more effort and</p><p>attention later in life [39].</p><p>Of note, in addition to being influenced by environmental stimuli, the various stages</p><p>of developmental neurogenesis and synaptogenesis are tightly regulated by numerous</p><p>intrinsic factors [32,34], including transcription factors, growth factors (such as brain-</p><p>derived neurotrophic factor (BDNF) and insulin-like growth factor (IGF)), cell adhesion</p><p>molecules (such as N-cadherin, which aids in cell migration and synaptic connection</p><p>formation), and signaling molecules (such as Notch, Sonic Hedgehog (SHH), Wnt, and</p><p>fibroblast growth factor (FGF)).</p><p>2.1.2. Adult Neurogenesis</p><p>Although the original evidence in support of adult neurogenesis dates back to the</p><p>1960s with the pioneering work of the American neuroscientist Joseph Altman [28], it was</p><p>Brain Sci. 2023, 13, 1610 4 of 32</p><p>only in the mid-1990s that this phenomenon became generally accepted [40] following the</p><p>seminal work by Eriksson et al. (1998), who demonstrated the incorporation of bromod-</p><p>eoxyuridine (BrdU; a nucleotide analog) into the DNA of newly generated neurons in the</p><p>human hippocampal dentate gyrus [41]. Since then, numerous studies have confirmed</p><p>that neural stem cells are indeed present in juvenile and adult brains [42] and that neu-</p><p>rogenesis continues to occur in select regions of the adult mammalian brain [14,43], the</p><p>most important and widely studied being the subgranular zone (SGZ) of the hippocampal</p><p>dentate gyrus [28] and the subventricular zone (SVZ) of the lateral ventricles [44]. Newborn</p><p>neurons have also been described in other brain regions, referred to as “noncanonical” neu-</p><p>rogenic areas [12], including the hypothalamus [45,46], neocortex [47,48], amygdala [49],</p><p>cerebellum [50,51], and striatum [42,52]. Of note, adult neurogenesis is thought to have</p><p>functional significance. For example, adult hippocampal neurogenesis is involved in several</p><p>emotional and cognitive functions, including spatial learning, memory, pattern separation,</p><p>and mood regulation [11,53–55].</p><p>Similarly to developmental neurogenesis, adult neurogenesis is also modulated by sev-</p><p>eral intrinsic and extrinsic factors, including trophic support [56,57], epigenetic factors [58],</p><p>physical activity [16], stress [59], environmental enrichment [14], and pharmacological inter-</p><p>ventions, such as antidepressants [60–62]. 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Wu, C.W.; van Gelderen, P.; Hanakawa, T.; Yaseen, M.A.; Duyn, J.H. Compensation after Stroke: Plasticity of Intrinsic Connectivity</p><p>Networks. Neuroimage 2021, 244, 118532.</p><p>363. Lövdén, M.; Schaefer, S.; Noack, H.; Kanowski, M.; Kaufmann, J.; Tempelmann, C.; Bodammer, N.C.; Kühn, S.; Heinze, H.-J.;</p><p>Lindenberger, U.; et al. Performance-Related Increases in Hippocampal N-Acetylaspartate (NAA) Induced by Spatial Navigation</p><p>Training Are Restricted to BDNF Val Homozygotes. Cereb. Cortex 2011, 21, 1435–1442. [CrossRef]</p><p>Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual</p><p>author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to</p><p>people or property resulting from any ideas, methods, instructions or products referred to in the content.</p><p>https://doi.org/10.5665/sleep.2802</p><p>https://doi.org/10.1093/brain/awab272</p><p>https://doi.org/10.5665/sleep.1846</p><p>https://doi.org/10.1016/S0166-2236(00)02002-6</p><p>https://doi.org/10.1093/cercor/bhq230</p><p>Introduction</p><p>Neuroplasticity</p><p>Structural Neuroplasticity</p><p>Developmental Neurogenesis and Synaptogenesis</p><p>Adult Neurogenesis</p><p>Functional Neuroplasticity</p><p>Neurodevelopment</p><p>and Neuroplasticity</p><p>Prenatal Stage (from Conception until Birth)</p><p>Infancy and Childhood</p><p>Adolescence</p><p>Adulthood</p><p>Prenatal Factors That Impact Neurodevelopment and Neuroplasticity</p><p>Postnatal Factors That Impact Neurodevelopment and Neuroplasticity</p><p>Sex Hormones and Neuroplasticity</p><p>Aging, Neurodegeneration, and Neuroplasticity</p><p>Physiological Aging</p><p>Neurodegeneration</p><p>Protein Aggregation in Neurodegeneration</p><p>Mitochondrial Dysfunction and Oxidative Stress in Neurodegeneration</p><p>Neuroinflammation in Neurodegeneration</p><p>Genetic and Environmental Factors in Neurodegeneration</p><p>Correlation between Aging, Neurodegeneration, and Neuroplasticity</p><p>Non-Pharmacologic and Non-Invasive Strategies to Promote Neuroplasticity during Aging</p><p>Physical Exercise</p><p>Cognitive Stimulation and Socialization</p><p>Diet and Caloric Restriction</p><p>Sleep Hygiene and Quality of Sleep</p><p>Conclusions</p><p>References</p><p>of plasticity but also has functional implications. The forma-</p><p>tion of new synapses or the strengthening of existing ones can enhance the communication</p><p>and transmission of signals among neurons, leading to functional changes in neuronal</p><p>circuits. These adaptations include two forms of synaptic plasticity, long-term potentiation</p><p>(LTP) and long-term depression (LTD), through which the strength of synaptic connections</p><p>between neurons can change in response to different patterns of neuronal activity, thus</p><p>contributing to memory formation, skill acquisition, and habituation [72]. According to this</p><p>hypothesis, learning or experiencing something new can strengthen synaptic connections.</p><p>This, in turn, increases the efficiency of synaptic neurotransmission, ultimately aiding in</p><p>memory consolidation and information recall [73,74].</p><p>The term LTP was first introduced in 1973 by Bliss and Lomo [75]. The authors</p><p>demonstrated the long-lasting increase of synaptic strength in the dentate gyrus of the</p><p>hippocampus following high-frequency stimulation. Later, in 1993, Bliss and Collingridge</p><p>expanded on these findings and discussed the potential implications of LTP in the context of</p><p>a cellular memory model [19]. LTP is one of the most well-studied mechanisms underlying</p><p>neuroplasticity and is a specific cellular and synaptic process in which the strength of</p><p>a synapse is increased, resulting in more efficient transmission of signals between the</p><p>presynaptic and the postsynaptic neurons. Mechanistically, LTP involves changes that</p><p>can last for an extended period (days, weeks, or even years) in the synaptic structure,</p><p>such as an increase in the size and shape of postsynaptic dendritic spines as well as the</p><p>increase in the area of postsynaptic density (PSD) and the number of neurotransmitter</p><p>receptors of the postsynaptic membrane in response to the calcium-dependent activation of</p><p>N-methyl-D-aspartate (NMDA) receptors [76]. LTP is often described using the principle</p><p>of Hebbian plasticity, which states that synapses that are repeatedly active at the same</p><p>time tend to strengthen their connections. This principle aligns with the idea that the</p><p>brain adapts to experiences and reinforces the neural pathways associated with those</p><p>experiences [77].</p><p>Brain Sci. 2023, 13, 1610 5 of 32</p><p>On the other hand, LTD is the process of decreasing synaptic strength, resulting in a</p><p>less efficient transmission of signals in response to the depolarization of the postsynaptic</p><p>neuron for an extended period. LTD helps maintain synaptic connections’ overall balance</p><p>and efficiency, which is essential for synaptic homeostasis [21]. Both LTP and LTD are</p><p>critical for the adaptative capabilities of the CNS and allow neural circuits to adjust their</p><p>connections and synaptic strength in response to experiences, cognitive function, memory</p><p>consolidation, and habituation [72,73].</p><p>In summary, functional and structural plasticity play an important role in brain func-</p><p>tion, and changes in neuroplasticity may be associated with diseases and disorders of the</p><p>CNS. It is worth noting that neuroplasticity is most robust during development, but it</p><p>persists throughout life. This fact has significant implications for understanding brain</p><p>function, recovery from brain injury, and potentially treating neurological and psychiatric</p><p>disorders.</p><p>3. Neurodevelopment and Neuroplasticity</p><p>The brain is arguably the most complex organ in the human body, and its devel-</p><p>opment is a continuous process that starts early in gestation and continues throughout</p><p>adulthood [78]. Neurodevelopment is a highly orchestrated process involving the pro-</p><p>liferation, migration, differentiation, and maturation of neurons and the formation and</p><p>refinement of synaptic connections between them [79]. Normal neurodevelopment is essen-</p><p>tial for the proper functioning of the nervous system, and any disruption in this process can</p><p>lead to a wide range of neurodevelopmental and neurological disorders, such as autism</p><p>spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), schizophrenia,</p><p>and epilepsy [80]. The causes of these disorders are complex and multifactorial, involving</p><p>genetic and environmental factors that can affect brain development and function [7]. Stud-</p><p>ies have shown that neuroplasticity involves many aspects of brain development, including</p><p>forming and refining neural connections during early development and acquiring new</p><p>skills and abilities throughout life [81,82]. In addition, neuroplasticity plays a crucial role in</p><p>recovery from brain injury and stroke and in treating neurological and psychiatric disorders,</p><p>such as depression and anxiety [83,84].</p><p>On the other hand, neuroplasticity disruptions can adversely affect neurodevelopment.</p><p>Exposure to toxic substances during development, such as alcohol or drugs, can impair</p><p>neuroplasticity and disrupt normal brain development [85,86]. Similarly, experiences with</p><p>chronic stress or trauma can impair neuroplasticity and lead to permanent changes in brain</p><p>structure and function [87]. Understanding the role of neuroplasticity in normal brain</p><p>development is critical for identifying and addressing factors that can disrupt this process</p><p>and lead to neurodevelopmental and neurological disorders. This section discusses the</p><p>stages of normal neurodevelopment and the factors influencing this process.</p><p>3.1. Prenatal Stage (from Conception until Birth)</p><p>Neurodevelopment is a critical process that begins approximately two to three weeks</p><p>after conception with the formation of the neural tube [88]. Neurulation involves the folding</p><p>and fusion of the lateral ends of the neural plate and is a crucial stage in the formation</p><p>of the brain and spinal cord. Abnormalities during neurulation can result in neural tube</p><p>defects, such as spina bifida [89]. Following neurulation, neurogenesis and neuronal</p><p>migration occur, which are also critical processes in neurodevelopment. Neurogenesis</p><p>occurs primarily during the first trimester of pregnancy and in specific brain regions, such</p><p>as the ventricular zone [29]. Neuronal migration occurs during the second trimester of</p><p>pregnancy. It is essential for proper brain development, allowing neurons to form correct</p><p>connections with other neurons and establish functional neural circuits [90].</p><p>During neurogenesis and neural migration, environmental factors such as stress,</p><p>nutrition, alcohol exposure, and sensory input can influence the rate and direction of these</p><p>processes. For example, exposure to stress hormones during gestation has been shown to</p><p>Brain Sci. 2023, 13, 1610 6 of 32</p><p>alter the timing of neurogenesis and the migration of new neurons, leading to changes in</p><p>brain structure and function [91].</p><p>Another significant event during embryonic development is the division of the neural</p><p>tube into three primary brain vesicles, which give rise to the different structures of the</p><p>brain [92]. Microglia migrate into the developing brain during the early stages of ges-</p><p>tation, around 4–5 weeks after fertilization, and establish the pool of resident immune</p><p>cells [93]. Gliogenesis, which produces region- and subtype-specific glia, begins at 22 weeks</p><p>of gestation and continues throughout adulthood [94]. Glial cells also aid in the myelina-</p><p>tion of neurons at approximately 32 weeks of pregnancy, a process that continues after</p><p>birth and into adulthood [95]. At 18 weeks of gestation, the excess of cells is eliminated</p><p>through apoptosis, a form of programmed cell death, resulting in the refinement of cell</p><p>populations and ensuring proper development and synaptic connectivity in the mature</p><p>brain [96]. Synaptogenesis begins in utero at approximately 27 weeks of gestation but</p><p>predominantly occurs after birth, coinciding with the growth of dendrites and axons and</p><p>axonal myelination [38]. The pruning of excess synapses and dendritic processes continues</p><p>after birth, a necessary process for proper neural network formation, with disruptions of</p><p>this step being linked to various neurological disorders [97]. By the end of the prenatal pe-</p><p>riod, major</p><p>fiber pathways, such as the thalamocortical pathway, have been established [34].</p><p>These critical stages of brain development are essential for a healthy and functional brain.</p><p>Conversely, disruptions in fetal brain development have been linked to an increased risk</p><p>of psychiatric disorders, such as autism and schizophrenia [98]. The complexity of these</p><p>processes highlights the importance of proper prenatal care, including good nutrition and</p><p>avoiding harmful substances such as alcohol and drugs, which can adversely affect brain</p><p>development [85,99].</p><p>The developmental origins of the health and disease hypothesis (DOHaD) propose</p><p>that environmental exposure during early life (particularly during the prenatal period)</p><p>can permanently influence the long-term development of disease. The initial studies</p><p>addressing this relationship observed the association between gestational malnutrition</p><p>and the phenotypes of the offspring, as well as the risk of developing metabolic diseases</p><p>such as obesity, diabetes, and cardiovascular diseases later in life. In accordance with</p><p>this, later studies have identified epigenetic modifications in fetal DNA as a response to</p><p>environmental stimuli, which can permanently alter protein expression and phenotypes in</p><p>the offspring. Of note, some of the environmental factors causing epigenetic modifications</p><p>besides maternal nutrition include smoking, maternal stress, and infection [100,101].</p><p>During prenatal development, genetic information plays a crucial role in orchestrating</p><p>events that determine the formation and refinement of neural connections. A complex</p><p>sequence of guidance molecules instructs newly born cells on what type of neurons to</p><p>become and where to go, while genetically determined intrinsic neural activity instructs the</p><p>refinement of axonal projections, which are guided by molecular cues to their approximate</p><p>target area [102]. While these events are critical for proper brain development, prenatal dis-</p><p>ruptions can negatively affect neuroplasticity. For example, prenatal exposure to teratogenic</p><p>factors such as alcohol can interfere with glutamatergic and GABAergic neurotransmitter</p><p>function, destabilizing previously tentative synapses [103,104]. This interference can lead</p><p>to structurally different yet functionally viable circuits. Studies have also shown that</p><p>neuroplastic changes during the prenatal period can have long-lasting effects on brain</p><p>development and behavior. For example, maternal stress during pregnancy has been linked</p><p>to altered brain development and increased risk for behavioral disorders such as ADHD</p><p>and ASD in the offspring, negatively impacting cognitive and emotional outcomes later in</p><p>life and increasing the risk for mental health conditions in adulthood [105].</p><p>Interestingly, through non-invasive techniques such as fetal magnetoencephalography</p><p>(fMEG) that record neural responses to external stimuli like music, speech, and touch [106],</p><p>it has been shown that exposure to music during the prenatal period can enhance the</p><p>development of the auditory system and improve cognitive function later in life [107]. In</p><p>addition, studies have shown that the fetus can recognize and respond to familiar voices,</p><p>Brain Sci. 2023, 13, 1610 7 of 32</p><p>including the mother’s voice. This recognition can be attributed to the development of the</p><p>auditory system, which is functional by the 16th week of gestation [108].</p><p>3.2. Infancy and Childhood</p><p>After birth, the human brain undergoes refinement and reorganization, particularly</p><p>during sensitive and critical periods known as “windows of brain plasticity,” which are</p><p>most pronounced in early childhood but continue into adolescence and adulthood [38].</p><p>During this stage, the brain undergoes an extraordinary growth spurt, with neurons form-</p><p>ing connections at an astonishing rate. As the brain triples in size during the first two years</p><p>of life, it builds an immense network of neural circuits that enables the processing of sen-</p><p>sory information and the development of higher-order cognitive functions [109]. Studies</p><p>have shown that early experiences and environmental factors are essential in shaping the</p><p>developing brain. For example, language development begins early in life. It involves a</p><p>complex interplay of genetic and environmental factors [110] and is strongly influenced by</p><p>early exposure to language and sounds [111,112].</p><p>Another critical aspect of neurodevelopment in childhood (as well as adolescence;</p><p>see below) is the development of executive skills such as attention, working memory, and</p><p>self-control. These skills are important for academic achievement, social functioning, and</p><p>well-being [113]. The development of executive functioning skills is influenced by several</p><p>factors, including genetics, environmental factors, and experiences [114]. Brain neuroplas-</p><p>ticity during infancy is also essential for developing social and emotional skills. Infants</p><p>develop the ability to recognize and respond to emotional cues and to form secure bonds</p><p>with caregivers. These skills, critical for social and emotional development, are shaped by</p><p>early experiences and essential for later well-being [115]. The growth and development</p><p>of the brain during this period lays the foundation for later cognitive, social, and emo-</p><p>tional abilities. Therefore, providing infants and children with a nurturing and stimulating</p><p>environment that promotes and supports optimal brain development is essential.</p><p>Windows of opportunity are necessary for developing new skills; however, they</p><p>leave the brain vulnerable to the harmful effects of the environment. In the same way</p><p>that environmental stimuli lead to necessary and expected neuronal remodeling while</p><p>learning a new skill that will be important throughout life, adverse situations can potentially</p><p>result in maladaptive changes. The World Health Organization (WHO) has coined the</p><p>term early stress to refer to adverse situations that occur during childhood, from birth to</p><p>18 years of age. Early stress can include coping with conditions such as living in extreme</p><p>poverty, violence, abuse (physical, sexual, or psychological), neglect, and grief, among</p><p>other examples. According to the WHO, around one billion children and adolescents are</p><p>exposed to some type of early stress every year [116,117]. When a child experiences a form</p><p>of early stress, the hypothalamic–pituitary–adrenal (HPA) axis is activated, resulting in the</p><p>release of cortisol, which in turn activates the sympathetic nervous system, thus triggering</p><p>the fight-or-flight response as a defense mechanism [118].</p><p>However, when the stress response is chronic and exacerbated, it leads to adverse</p><p>effects, including deregulating the HPA axis. Indeed, the sustained release of high levels of</p><p>cortisol into the blood plasma can result in the disruption of the feedback loop that regulates</p><p>the HPA axis, causing resistance to cortisol and ultimately resulting in the damage of various</p><p>brain regions, including the hippocampus [119,120]. Indeed, when in excess, cortisol (or</p><p>corticosterone in rodents) causes damage to dendritic arborization, the morphology of</p><p>dendritic spines, and the synaptic integrity of hippocampal neurons. Male C57BL/6N mice</p><p>that were subjected to an environmental stress protocol (insufficient sawdust in the housing</p><p>box) between postnatal days 2 and 9 showed decreased arborization and lower density</p><p>of dendritic spines in pyramidal neurons in the CA3 region of the hippocampus [121].</p><p>Furthermore, exposure to early stress induces decreased neurogenesis in the dentate gyrus</p><p>of the hippocampus in C57 adult mice [122].</p><p>Notably, the impact of hyperactivation of the HPA axis on brain morphology and</p><p>behavior (including the development of self-destructive behaviors, less tolerance to adverse</p><p>Brain Sci. 2023, 13, 1610 8 of 32</p><p>everyday situations, greater vulnerability to substance abuse, and difficulties in interper-</p><p>sonal relationships) is well documented in the literature [123,124]. Indeed, reductions in</p><p>adult neurogenesis, dendritic arborization, and glucocorticoid receptor</p><p>density changes</p><p>have been observed in the hippocampus of adults who experienced early stress [124,125].</p><p>Furthermore, exposure to early stress has also been associated with decreased gray matter</p><p>and increased psychiatric disorders, including anxiety and depression [126]. Further-</p><p>more, studies have demonstrated the relationship between the experience of early stress</p><p>in childhood and the development of alcohol dependence later in life [127]. A survey of</p><p>3592 adults on their drinking habits and history of early stress showed that the average</p><p>age at which alcohol intake began was lower in people with traumatic experiences. While</p><p>most participants said they drink to socialize and feel good, around 10% said they use</p><p>alcohol to “deal with problems and stress” [128]. In addition, Pilowsky and collaborators</p><p>(2009) demonstrated an association between traumatic events occurring in childhood and</p><p>adolescence with a greater frequency of heavy episodic drinking and an early onset of</p><p>alcohol consumption, with data highlighting that experiencing two or more traumatic</p><p>events early in life increased the propensity for alcohol dependence in adulthood. The</p><p>chronicity and severity of these episodes were also associated with the risk of relapse in</p><p>female patients who were undergoing treatment for cocaine addiction [129,130].</p><p>3.3. Adolescence</p><p>As children grow into adolescence, their brains mature, accompanied by significant</p><p>cognitive, social, and emotional development. Indeed, neuroimaging studies have shown</p><p>that the adolescent brain undergoes considerable changes in the prefrontal cortex, which is</p><p>responsible for higher-order cognitive functions, such as decision making, impulse control,</p><p>attention, and working memory [131]. The prefrontal cortex is also involved in social and</p><p>emotional processing, and its development during adolescence is crucial for acquiring</p><p>social and emotional skills, including navigating complex social relationships, empathizing</p><p>with others, and regulating emotions. Indeed, the prefrontal cortex undergoes significant</p><p>changes in its structural and functional connectivity during adolescence, and these changes</p><p>have been related to improvements in social cognition and emotion regulation [132,133].</p><p>Moreover, recent studies have highlighted the role of the social brain network, which</p><p>includes regions such as the medial prefrontal cortex, the temporoparietal junction, and</p><p>the amygdala, in social and emotional processing during adolescence [134,135]. These</p><p>brain regions are involved in social cognition, empathy, and emotional regulation, and their</p><p>development during adolescence is crucial for social and emotional competence.</p><p>Understanding the neurobiological changes during adolescence is crucial for promot-</p><p>ing healthy brain development and preventing mental health conditions during this critical</p><p>period of life. One of the most significant changes during adolescence is synaptic pruning,</p><p>which involves the elimination of unnecessary synapses and neural connections. This</p><p>process makes the brain more efficient by reducing neural noise and enhancing information</p><p>processing [136]. Synaptic pruning occurs mainly in the prefrontal cortex but also affects</p><p>other brain regions, such as the hippocampus and amygdala [37].</p><p>3.4. Adulthood</p><p>In adulthood, the rate of neurodevelopment slows down significantly. However,</p><p>the brain retains the capacity to form new neurons and connections and adapt to new</p><p>experiences throughout life. One mechanism through which the brain can continue to</p><p>adapt is adult neurogenesis, which is thought to play an important role in learning and</p><p>memory, as well as in mood regulation and the stress response [11,53–55].</p><p>In addition to the hippocampus and the SVZ, additional brain regions have also</p><p>emerged as sites where adult neurogenesis can take place [12]. Indeed, animal studies</p><p>have delineated neurogenic loci encompassing the hypothalamus [137], striatum [138–140],</p><p>substantia nigra (SN) [141], cerebral cortex [142], and amygdala [143]. Evidence indicates</p><p>that the genesis of neurons in these newly identified neurogenic areas is attributable to</p><p>Brain Sci. 2023, 13, 1610 9 of 32</p><p>the migration of NSPCs, typically originating from the SVZ [140,143–147]. Concurrently,</p><p>some studies have challenged this notion and proposed the existence of endogenous pools</p><p>of NSPCs within these regions, capable of local replication and integration into neuronal</p><p>circuits [137,138,148,149].</p><p>The hypothalamus, one of the major regulatory centers in the brain, controls various</p><p>homeostatic processes, and hypothalamic neural stem cells (htNSCs) have been shown to in-</p><p>terfere with these processes. Indeed, the hypothalamic neurogenesis is thought to influence</p><p>metabolism and fat storage, as evidenced by multiple studies on the impacts of a high-fat</p><p>diet (HFD) in mice [46,150,151]. Furthermore, neurogenesis within the hypothalamus is</p><p>also thought to contribute to behavioral and sexual functions, as elucidated in studies</p><p>by Bernstein et al. (1993) [152], Fowler et al. (2002) [153], and Cheng et al. (2004) [154].</p><p>Additionally, emerging research suggests that neurogenesis in the hypothalamus undergoes</p><p>alterations during aging [155], prompting investigations into the potential implications of</p><p>age-related changes in hypothalamic neurogenesis on overall physiological homeostasis</p><p>and cognitive functions [156].</p><p>Of note, deficits in adult hippocampal neurogenesis (as well as other forms of struc-</p><p>tural and functional plasticity) have been implicated not only in normal aging [63], but</p><p>also in various psychiatric [69] and neurodegenerative [70,71] conditions. Conversely,</p><p>classic antidepressants such as monoamine oxidase inhibitors (MAOIs), tricyclic antide-</p><p>pressants, and selective serotonin reuptake inhibitors (SSRIs) have been shown to possess</p><p>pro-neurogenic properties, and these are thought to mediate, at least in part, their antide-</p><p>pressant effects [60,61,157,158]. More recently, ketamine, an anesthetic with antidepressant</p><p>properties, was also shown to increase adult hippocampal neurogenesis in rodents [159].</p><p>Other studies have explored the potential of environmental enrichment (such as exposing</p><p>animals to a stimulating environment with toys and social interactions) [8,14,160] and</p><p>physical exercise [160–162] in promoting adult hippocampal neurogenesis. These findings</p><p>highlight the exciting potential of pharmacologic and non-pharmacologic interventions in</p><p>promoting adult hippocampal neurogenesis and potentially improving human brain health</p><p>and cognitive function.</p><p>3.5. Prenatal Factors That Impact Neurodevelopment and Neuroplasticity</p><p>Several prenatal factors can significantly impact neurodevelopment, and multiple</p><p>lines of research have identified maternal nutrition, exposure to toxins (e.g., alcohol and</p><p>illicit drugs), and infection as crucial determinants. Insufficient nutrition during preg-</p><p>nancy can lead to low birth weight and impaired cognitive development [163]. Moreover,</p><p>maternal nutrition has been associated in preclinical and clinical research with altered</p><p>neuropsychiatric outcomes in the offspring [164,165]. Of note, insulin has been identified as</p><p>a critical modulator of neuronal network development during the early phases of life [166].</p><p>Studies have shown an association between impaired insulin signaling in the hippocam-</p><p>pus of adolescent and adult offspring of obese mice with impairments in hippocampal</p><p>gene expression, neurogenesis, and synaptic plasticity [167–170]. Furthermore, a recent</p><p>study in rodents also suggested that an appropriate maternal diet, especially fiber-rich,</p><p>could regulate and reverse these neurocognitive alterations [170]. One possible mechanism</p><p>underlying the effects of a maternal high-fat diet on these neurodevelopment outcomes</p><p>is related to altered Notch 1 signaling activation, which in turn is thought to inhibit the</p><p>proliferation and differentiation of neural progenitors [171]. In addition, maternal excess</p><p>salt intake has also been associated with changes in brain development and neural plas-</p><p>ticity in rodents, particularly concerning synaptic transmission and neuroplasticity in the</p><p>hippocampus [172].</p><p>Exposure to toxins, including alcohol, illicit drugs, and heavy metals such as lead,</p><p>significantly impacts the developing brain, potentially resulting in brain damage and devel-</p><p>opmental delays [173]. These toxic substances can enter the body through various sources,</p><p>including environmental pollution, contaminated food and water, and maternal substance</p><p>use. Alcohol exposure during pregnancy has been linked to fetal alcohol spectrum disor-</p><p>Brain Sci. 2023, 13, 1610 10 of 32</p><p>ders (FASDs), a range of neurodevelopmental and behavioral problems that can result in</p><p>lifelong disabilities and neurocognitive abnormalities [85,174].</p><p>Consumption of cannabis (marijuana) during the prenatal period has also been shown</p><p>to affect neurodevelopmental processes. Indeed, in utero exposure to ∆9-tetrahydrocannabinol</p><p>was associated with behavioral alterations in adolescent rats, including impairment in aver-</p><p>sive limbic memory, decreased instrumental learning, and increased alcohol</p><p>consumption [175]. Similarly, exposure to illicit drugs, including stimulants (such as</p><p>cocaine and methamphetamine) and opioids (such as heroin), can cause a range of adverse</p><p>effects, including congenital disabilities, low birth weight, and developmental delays [176].</p><p>Exposure to heavy metals can also cause irreversible damage to the developing brain,</p><p>leading to a range of cognitive, behavioral, and developmental problems [177]. Maternal</p><p>infections during pregnancy can also have severe consequences for fetal development.</p><p>For example, rubella infection during pregnancy can lead to congenital malformations,</p><p>including hearing loss and intellectual disabilities [178]. Although the association between</p><p>COVID-19 and congenital anomalies in babies conceived and born during the pandemic is</p><p>still unclear due to the lack of knowledge on fetal and perinatal complications following</p><p>COVID-19 infection, some studies have shown an increase in the rate of CNS congenital</p><p>anomalies during the pandemic [179–181]. The long-term neuroplastic changes caused by</p><p>COVID-19 infections are still unclear and require further investigation.</p><p>3.6. Postnatal Factors That Impact Neurodevelopment and Neuroplasticity</p><p>After birth, several postnatal factors can significantly influence neurodevelopment</p><p>and neuroplasticity. Nutrition, social interaction, and environmental factors can all affect</p><p>brain development during the postnatal period. Nutritional status is a critical determinant</p><p>of brain growth and development, particularly during the first 1000 days of life [182]. In</p><p>rodents, a high-fat diet during the postnatal period can negatively impact cognition and</p><p>synaptic plasticity and promote neuroinflammation and microglial activation [183]. For</p><p>example, ingestion of sweeteners, such as aspartame and sucralose, can induce changes</p><p>in behavior and neuroplasticity, including decreases in hippocampal neurogenesis and</p><p>BDNF levels in rats in a sex-dependent manner [184]. In humans, breastfeeding has been</p><p>associated with improved metabolic and neurocognitive health outcomes in infants [185],</p><p>effects that are thought to be mediated, at least in part, by the unique properties and</p><p>lipid composition of maternal milk [186]. In addition, several studies have shown that</p><p>inadequate nutrition during infancy and early childhood can lead to long-term cognitive</p><p>deficits, reduced academic achievement, and behavioral problems [187,188]. In contrast,</p><p>adequate nutrition during this period can promote optimal brain development, including</p><p>improved cognitive and behavioral outcomes [189,190].</p><p>As explained above (see Section 3.2), the early years of life are a period of significant</p><p>neuroplasticity, and experiences during this time can shape the structure and function</p><p>of the brain [191]. Social interaction and early childhood experiences, such as language</p><p>exposure, are critical for optimal brain development. Studies have shown that children</p><p>who experience high-quality early care and education, including language-rich environ-</p><p>ments, have better cognitive, social–emotional, and academic outcomes than those who</p><p>do not [192,193]. Conversely, lack of stimulation, social deprivation, and neglect can have</p><p>long-lasting adverse effects on brain development, including reduced cortical thickness</p><p>and gray matter volume [194] and increased risk of cognitive deficits and developmental</p><p>delays [195].</p><p>Life experience and environmental enrichment positively modulate behavior and neu-</p><p>roplasticity during critical periods and throughout life [36,196]. Environmental enrichment</p><p>during childhood, adolescence, and adulthood has been shown to promote neurogenesis</p><p>and affect the pattern of monosynaptic inputs in animal models [14,160,197]. Additionally,</p><p>environmental enrichment has been shown to improve spatial learning performance and</p><p>neuroplasticity while increasing hippocampal volume and BDNF levels in various animal</p><p>models [160,198]. In humans, evaluating the impact of environmental enrichment on brain</p><p>Brain Sci. 2023, 13, 1610 11 of 32</p><p>neuroplasticity and function is much more complex due to the number of potential con-</p><p>founding variables. However, a recent randomized control trial has assessed the effects</p><p>of environment and neurodevelopment and concluded that interventions that can reduce</p><p>poverty could promote changes in children’s brain function and the development of higher-</p><p>order cognitive skills. This study found that infant neuroplasticity was positively correlated</p><p>with economic status, which in turn is known to impact numerous socio-economic factors</p><p>that can influence a child’s well-being, including household income and expenses, type</p><p>and amount of work of the mother, parenting behavior, and overall family wellbeing and</p><p>stress [199]. Social interactions can also be considered a form of environmental enrichment</p><p>known to modulate neuroplasticity. In particular, maternal contact has been shown to im-</p><p>pact neurodevelopment and to have long-lasting effects on behavior. Appropriate maternal</p><p>care during the first postnatal week can promote life-long stress resilience in rodents [200].</p><p>In conclusion, neuroplasticity is a critical determinant of brain growth and develop-</p><p>ment not only prenatally but also during the postnatal period. Several prenatal factors,</p><p>such as maternal nutrition, exposure to toxins, and infection, can potentially result in or</p><p>contribute to the offspring’s cognitive, behavioral, and developmental problems. On the</p><p>other hand, an appropriate maternal diet, especially one rich in fiber, can help prevent neu-</p><p>rocognitive alterations caused by a maternal high-fat diet. The early years of postnatal life</p><p>are also particularly significant for brain development, as experiences during this time can</p><p>shape the structure and function of the brain. Adequate nutrition, language-rich environ-</p><p>ments, high-quality early care, education, and rewarding social interactions and stimulation</p><p>are critical for optimal brain development during this period. Environmental enrichment</p><p>during childhood and adolescence can increase neuroplasticity and improve cognitive</p><p>outcomes. In contrast, exposure to toxins, social deprivation, neglect, and harmful environ-</p><p>mental factors can have a long-lasting negative impact on brain development, potentially</p><p>leading to long-term cognitive deficits and behavioral and psychological disturbances.</p><p>3.7. Sex Hormones and Neuroplasticity</p><p>Sex hormones are now known to have widespread actions in both the male and female</p><p>brains, through mechanisms thought to involve both genomic and nongenomic receptors.</p><p>Indeed, many neural and behavioral functions are affected by sex hormones such as estro-</p><p>gens, including mood, cognitive function, blood pressure regulation, motor coordination,</p><p>pain, and opioid sensitivity [201]. Moreover, sex-specific differences have been reported</p><p>with regards to hippocampal-dependent cognition and neurogenesis, suggesting that sex</p><p>hormones are involved in these processes.</p><p>Indeed, estrogens have been shown to modulate</p><p>certain forms of spatial and contextual memory, as well as different forms of neuroplasticity</p><p>including neurogenesis, primarily in the adult female hippocampus [202,203].</p><p>Peripheral sex steroid hormones, including estrogens, progesterone, testosterone, and</p><p>other androgens, are able to cross the blood–brain barrier and reach the brain. Furthermore,</p><p>hippocampal neurons are capable of synthesizing sex steroids de novo from cholesterol,</p><p>since neural cells express all the enzymes required for the synthesis of estradiol and testos-</p><p>terone, the end products of sex steroidogenesis [204–209]. Regarding 17β-estradiol (E2)</p><p>in particular, its synthesis in hippocampal neurons is homeostatically controlled by Ca2+</p><p>transients and is regulated by the release of gonadotropin-releasing hormone (GnRH) [210].</p><p>Indeed, release of GnRH from GnRH-positive neurons in the hippocampus is thought to</p><p>regulate the local synthesis of sex steroids in a sex-dependent manner and thus contribute</p><p>to the sexual differentiation of hippocampal neurons during the perinatal period [210,211].</p><p>Of note, a GnRH-induced increase in estradiol synthesis appears to provide a link between</p><p>the hypothalamus and the hippocampus, and this may underlie, at least in part, estrous</p><p>cyclicity of spine density in the female hippocampus [206,210]. Furthermore, sex hormones</p><p>can initiate gene transcription and activate signaling cascades by utilizing genomic and</p><p>non-genomic [201,212] mechanisms that play a key role in coordinating various physio-</p><p>logical and pathological neuroplasticity-related events, such as formation or remodeling</p><p>of dendritic spines, neurogenesis, synaptogenesis, and myelination modulation [213]. For</p><p>Brain Sci. 2023, 13, 1610 12 of 32</p><p>example, the study by Lu et al. in 2019, employing a forebrain-neuron-specific aromatase</p><p>knock-out mouse model, provided compelling genetic evidence of the involvement of</p><p>neuron-derived E2 in modulating AKT-ERK and CREB-BDNF signaling cascades. This</p><p>study established that neuron-derived E2 is essential for normal expression of LTP and</p><p>other forms of synaptic plasticity, as well as cognitive function in both male and female</p><p>brains [214]. However, it has also been proposed that whereas E2 appears to be essential</p><p>to maintaining synaptic transmission and synaptic connectivity in the female hippocam-</p><p>pus, dihydrotestosterone appears to be crucial for synaptic transmission and synaptic</p><p>connectivity in the male hippocampus [207,210,211]. As the expression of sex hormones</p><p>varies throughout the lifespan, its effects on neuroplasticity during distinct periods of</p><p>development, adulthood, and aging must also be considered. Along these lines, strategies</p><p>aimed at restoring and/or maintaining normal hormone levels in the brain throughout the</p><p>lifespan such as physical exercise are thought to be beneficial in promoting brain health in</p><p>general and neuroplasticity in particular [215].</p><p>4. Aging, Neurodegeneration, and Neuroplasticity</p><p>4.1. Physiological Aging</p><p>Aging is a natural process affecting various physiological systems, including the</p><p>immune, cardiovascular, musculoskeletal, and nervous systems [216]. According to the</p><p>United Nations, the proportion of people over 60 is projected to reach 25% by 2050 [217,218],</p><p>reflecting a global trend towards population aging. As the population ages worldwide, the</p><p>incidence of age-related diseases and the associated healthcare costs also increase.</p><p>The World Health Organization (WHO) defines healthy aging as the process of opti-</p><p>mizing opportunities for physical, mental, and social well-being to enable older individuals</p><p>to maintain their functional abilities that allow them to participate actively in society [219].</p><p>This definition encompasses not only the absence of disease but also emphasizes the im-</p><p>portance of maintaining functional capacity and engagement in activities that contribute</p><p>to a fulfilling life. For older adults, healthy aging involves healthy lifestyle habits and</p><p>behaviors, including healthy nutrition, regular physical activity, and avoiding smoking,</p><p>excessive drinking, and illicit drugs.</p><p>Aging increases the risk of developing chronic diseases such as cardiovascular disease,</p><p>diabetes, and cancer. For example, type 2 diabetes is more prevalent in older adults,</p><p>with approximately one in four adults over the age of 65 being affected by this metabolic</p><p>disorder [220]. Cancer incidence also increases with age, with approximately 60% of</p><p>all cancer cases occurring in adults over the age of 65 [221]. Moreover, ischemic heart</p><p>disease, stroke, and chronic obstructive pulmonary disease (COPD) are common causes</p><p>of mortality in the elderly population [222]. Additionally, aging is characterized by a</p><p>decline in immune function linked to the accumulation of senescent cells, which secrete</p><p>pro-inflammatory cytokines and contribute to chronic inflammation, ultimately resulting</p><p>in tissue damage [223]. Indeed, aging is associated with cellular senescence, a state of</p><p>irreversible growth arrest, which can be induced by various stressors, such as oxidative</p><p>stress, resulting in the damage of cellular proteins, lipids, and DNA [224], as well as</p><p>telomere shortening [225].</p><p>One of the critical differences between physiological and pathological brain aging</p><p>relates to cognitive reserve and the maintenance of cognition in physiological aging versus</p><p>the presence of notable cognitive decline in pathological aging. Indeed, the intrinsic</p><p>capacity of the nervous system to regenerate and compensate for neuronal loss (i.e., the</p><p>“brain reserve”) may counteract neurodegeneration and its consequences [226]. Within this</p><p>scenario, environmental (e.g., lifestyle) and genetic factors influence the degree of resiliency</p><p>to aging, thus influencing how much the intrinsic “brain reserve” can help prevent age-</p><p>related neuronal damage and loss. Cognitive reserve depends on how efficiently the system</p><p>can tap into the brain reserve [227]. In animal studies, several intrinsic and extrinsic factors,</p><p>including sex, body weight, physical activity, sleep duration, and anxiety and stress, can all</p><p>affect the cognitive reserve and the onset of cognitive impairments with aging [228].</p><p>Brain Sci. 2023, 13, 1610 13 of 32</p><p>On the other hand, regulation of neuroinflammation and oxidative stress, as well as</p><p>maintenance of calcium homeostasis, can promote cellular resilience and neuronal circuit</p><p>adaptation and ultimately increase cognitive reserve [229–231]. Nevertheless, the aging</p><p>brain does experience significant structural and functional changes, particularly affecting</p><p>the hippocampus and cerebral cortex [63,232]. Depending on the cognitive reserve of the</p><p>brain, alterations in neurons and their connectivity may decrease cognitive function [63]</p><p>and increase the risk of developing age-related neurological disorders such as AD and</p><p>Parkinson’s disease (PD) [233–236].</p><p>In addition to affecting neuronal structure and function, aging has also been associated</p><p>with astrocytic dysfunction and subsequent synaptic disturbances. Indeed, in old animals,</p><p>deficiencies in astrocytic glutamate uptake have been related to synaptic plasticity im-</p><p>pairments and age-related cognitive decline. Furthermore, astrocytes’ role in maintaining</p><p>antioxidant defenses may also be compromised by aging, which can further contribute to</p><p>neurodegeneration [237].</p><p>In addition, microglia (immune cells of the brain) and oligodendrocytes (myelinating</p><p>cells of the CNS) are also affected by aging. Indeed, an age-related reduction in both white</p><p>matter volume, myelinization, and microglia activation has been observed in the aged</p><p>brain, with an impairment in microglia activation being associated with decreased neuro-</p><p>protection and a compromised process of synapse elimination [237]. Neuroinflammation</p><p>is a well-established contributor to age-related cognitive impairments and hippocampal</p><p>neurogenesis deficits. The production of inflammatory mediators, including cytokines,</p><p>interleukins, and neurotrophins, as well as the activation</p><p>of glia and other immune cells,</p><p>can have a direct impact on synaptic plasticity and neurogenesis and with that exacerbate</p><p>the processes associated not only with normal aging but also with neurodegenerative</p><p>disorders [238,239].</p><p>One of the most notable changes associated with aging is mitochondrial dysfunction.</p><p>With age, mitochondria become less efficient at producing adenosine triphosphate (ATP)</p><p>and more prone to producing toxic reactive oxygen species (ROS) [216], which in turn can</p><p>cause neuronal dysfunction and, ultimately, cell death. Dysregulation of mitochondrial</p><p>function contributes to the pathogenesis of age-related diseases, including neurodegen-</p><p>erative disorders. Indeed, mitochondrial dysfunction has been implicated in AD and</p><p>PD [240]. The accumulation of mitochondrial DNA mutations has been observed in aged</p><p>mice, and this has been linked to increased oxidative damage [241]. Intracellular Ca2+</p><p>dysregulation has also been implicated in age-related cognitive decline [242,243]. Indeed,</p><p>an increase in intracellular Ca2+ levels in dorsal hippocampus CA1 pyramidal neurons</p><p>has been shown to contribute to memory impairment in aged animals [244]. Furthermore,</p><p>reduced NMDA receptor activation and LTP can impair Ca2+-dependent synaptic plasticity</p><p>in old animals [245].</p><p>Interventions targeting the various physiological systems affected by aging may in-</p><p>crease the lifespan and improve the quality of life of older individuals. For example,</p><p>physical exercise has been shown to improve cardiovascular function, increase neuroplas-</p><p>ticity, and promote the production of anti-inflammatory cytokines, all of which can help</p><p>mitigate the adverse effects of aging on the body and the brain [246,247]. Furthermore,</p><p>promoting healthy lifestyle habits such as maintaining a nutritious diet, engaging in regular</p><p>physical exercise, and avoiding smoking and excessive alcohol consumption can also help</p><p>minimize the impact of aging on individuals and society [63,162]. Indeed, maintaining</p><p>functional capacity and improving well-being can enhance the quality of life for older</p><p>individuals and drastically reduce healthcare costs.</p><p>4.2. Neurodegeneration</p><p>Neurodegeneration is characterized by the progressive loss of neuronal structure and</p><p>function, leading to irreversible neuronal damage and cell death [248]. Neurodegeneration</p><p>underlies the development of several neurodegenerative diseases, including AD, PD, as</p><p>well as HD, and amyotrophic lateral sclerosis (ALS) [249–251]. Neurodegenerative diseases</p><p>Brain Sci. 2023, 13, 1610 14 of 32</p><p>affect millions worldwide, with AD and PD being the most common neurodegenerative</p><p>disorders. In the United States, as many as 6.2 million people may have AD, as reported by</p><p>the Alzheimer’s Disease Association in 2022 [252]. Similarly, nearly a million Americans</p><p>are living with PD, according to the Parkinson’s Foundation [253]. The incidence of these</p><p>disorders is expected to triple by 2050, highlighting the need for effective prevention and</p><p>treatment strategies [254].</p><p>Multiple factors are known to contribute to the neurodegenerative processes that</p><p>culminate in neuronal damage and, ultimately, cell death [238,255]. For example, protein</p><p>misfolding, aggregation, and deposition have long been recognized as neuropathological</p><p>hallmarks common to many neurodegenerative disorders, including AD, PD, HD, and</p><p>ALS [250,256–258]. Moreover, mitochondrial dysfunction (which can result from genetic</p><p>mutations, exposure to environmental toxins, as well as physiological aging) [259], ROS</p><p>generation and accumulation, and a consequent increase in oxidative stress [250,260,261]</p><p>have all been shown to play a role in the pathogenesis of several neurodegenerative</p><p>disorders, including AD, PD, and HD. In addition, neuroinflammation has also been</p><p>implicated in the development of neurodegenerative diseases [262–264]. Other factors</p><p>contributing to aging and neurodegeneration (and consequent neuroplasticity impairment)</p><p>include genetic and environmental factors [236].</p><p>4.2.1. Protein Aggregation in Neurodegeneration</p><p>Neurodegenerative diseases are characterized by the accumulation and aggregation of</p><p>disease-specific proteins such as beta-amyloid and tau in AD, alpha-synuclein in PD, and</p><p>mutant huntingtin in HD [265]. These proteins misfold and form toxic oligomers and fibrils</p><p>that interfere with normal cellular functions, eventually leading to cell death. This process is</p><p>known as protein aggregation. The formation of abnormal protein aggregates is believed to</p><p>arise from disturbances in the proteostasis network. This tightly regulated system ensures</p><p>proper protein folding, trafficking, and degradation under normal conditions [266]. Disrup-</p><p>tions to the proteostasis network can result from genetic mutations, aging, environmental</p><p>stimuli, or a combination of several factors. Such disruptions can trigger the accumulation</p><p>of misfolded proteins, formation of protein aggregates, increased neuroinflammation and</p><p>oxidative stress, and activation of apoptotic pathways, ultimately culminating in neuronal</p><p>death.</p><p>The endoplasmic reticulum (ER) is a critical component of the proteostasis network</p><p>and is involved in the folding and processing of proteins [267]. Disruptions to ER func-</p><p>tion can accumulate misfolded proteins and trigger ER stress, activating the unfolded</p><p>protein response (UPR) [268]. The UPR signaling pathway activates adaptive pathways</p><p>to improve protein folding and promote quality control mechanisms and degradative</p><p>pathways [269]. Recent studies have shown that the UPR plays a role in the pathogenesis</p><p>of neurodegenerative diseases. For example, in AD, the UPR is activated in response to</p><p>the accumulation of beta-amyloid [270], while in PD, it is activated in response to the</p><p>accumulation of alpha-synuclein [271]. However, if the UPR fails to restore proteostasis or</p><p>if the accumulation of misfolded proteins exceeds the capacity of the cellular machinery to</p><p>degrade them, the UPR can also activate apoptotic pathways, thus resulting in neuronal</p><p>death [266].</p><p>4.2.2. Mitochondrial Dysfunction and Oxidative Stress in Neurodegeneration</p><p>Oxidative stress and mutations in mitochondrial DNA contribute to aging and neu-</p><p>rodegenerative diseases [272]. Several studies have shown that mitochondrial DNA muta-</p><p>tions accumulate in the aging brain and are associated with cognitive decline [261,273,274].</p><p>Moreover, increased levels of ROS have been shown to induce mitochondrial DNA mu-</p><p>tations and damage the mitochondrial respiratory chain, leading to mitochondrial dys-</p><p>function and neuronal death [275–277]. Furthermore, recent studies have shown that the</p><p>crosstalk between oxidative stress and other pathological mechanisms, such as protein</p><p>Brain Sci. 2023, 13, 1610 15 of 32</p><p>misfolding and inflammation, can further exacerbate mitochondrial damage and neuronal</p><p>death [278].</p><p>An increasing number of disease-specific proteins have been found to interact with</p><p>mitochondria. For example, mutant huntingtin has been shown to disrupt mitochondrial</p><p>function and dynamics in HD [279]. Moreover, dysfunctional mitochondria may precipitate</p><p>AD since beta-amyloid disrupts mitochondrial function and impairs energy production</p><p>in brain cells [280,281]. PD is also associated with mitochondrial dysfunction, including</p><p>impaired mitochondrial dynamics and oxidative stress [282], and oxidative stress has</p><p>been linked to alpha-synuclein accumulation in dopaminergic neurons, a hallmark of the</p><p>disease [283]. Together, these studies suggest that mitochondrial dysfunction is involved in</p><p>the pathogenesis of multiple neurodegenerative disorders.</p><p>4.2.3. Neuroinflammation in Neurodegeneration</p><p>Neuroinflammation is a complex process mediated by microglia and astrocytes and is</p><p>thought to play a role in several neurodegenerative diseases [284]. Microglia can assume</p><p>phagocytic phenotypes and release inflammatory cytokines in response to various stimuli,</p><p>including protein aggregates and pathogens [285]. For example, protein aggregates, such</p><p>as beta-amyloid in AD and alpha-synuclein in</p><p>PD, can activate microglia and induce</p><p>chronic neuroinflammation, leading to neuronal dysfunction and death [286,287]. Moreover,</p><p>oligomeric aggregates of beta-amyloid, tau, and alpha-synuclein can initiate both glial</p><p>and neuronal inflammation by activating several inflammatory pathways [286,288,289]. In</p><p>agreement, a recent study has shown that induced peripheral inflammation can potentiate</p><p>the adverse effects of alpha-synuclein oligomers by exacerbating neuroinflammation and</p><p>cognitive deficits in a synucleinopathy mouse model [290].</p><p>In response to injury or inflammation, activated astrocytes (i.e., astrogliosis) can also</p><p>contribute to neuroinflammation by releasing cytokines and chemokines, further activating</p><p>microglia and perpetuating neuroinflammation [291]. In agreement, a recent study showed</p><p>that activated microglia can promote the activation of neurotoxic reactive astrocytes (A1</p><p>type), resulting in both neuron and oligodendrocyte death. Of note, reactive A1 astrocytes</p><p>have been reported in various neurodegenerative diseases, including AD, PD, HD, ALS,</p><p>and multiple sclerosis [287]. In animal models of AD, reactive astrocytes were associated</p><p>with atrophy of glial fibrillary acidic protein (GFAP)-positive cells and the presence of</p><p>amyloid deposits in brain regions such as the hippocampus [292].</p><p>4.2.4. Genetic and Environmental Factors in Neurodegeneration</p><p>Genetic and environmental factors can also contribute to neuroinflammation and</p><p>neurodegeneration [293]. For example, mutations in the triggering receptor expressed on</p><p>the myeloid cells 2 (TREM2) gene, expressed by microglia, have been linked to an increased</p><p>risk of AD and other neurodegenerative diseases [294]. Moreover, genome-wide association</p><p>studies have identified new genetic risk factors for AD and PD [295].</p><p>In addition, environmental factors such as exposure to toxins, infection, and traumatic</p><p>brain injury (TBI) have also been shown to increase the risk of various neurodegenerative</p><p>diseases [296–298]. For example, exposure to pesticides, heavy metals, and solvents has</p><p>been linked to increased incidence of AD and PD [296]. Viral infections, such as herpes</p><p>simplex virus type 1 and human herpes virus 6, have also been associated with the de-</p><p>velopment of AD [297]. Furthermore, TBI has been linked to the development of chronic</p><p>traumatic encephalopathy, a neurodegenerative disease commonly found in athletes and</p><p>military veterans [298].</p><p>4.3. Correlation between Aging, Neurodegeneration, and Neuroplasticity</p><p>Several lines of evidence have supported a strong correlation between aging, neu-</p><p>rodegeneration, and neuroplasticity. With age, both neurogenesis (i.e., the generation of</p><p>new neurons) and synaptic plasticity (i.e., the ability of neurons to form new connections)</p><p>decline [299]. These changes are thought to contribute to the development and progression</p><p>Brain Sci. 2023, 13, 1610 16 of 32</p><p>of neurodegenerative processes by impairing the ability of the brain to compensate for the</p><p>effects of physiological aging and/or incurred damage while maintaining normal function.</p><p>On the other hand, engaging in activities that promote neuroplasticity, such as learning new</p><p>skills or engaging in regular physical exercise, has been shown to help maintain cognitive</p><p>function and slow cognitive decline in older adults [162,300]. These findings suggest that</p><p>interventions designed to enhance neuroplasticity may slow or potentially reverse the</p><p>effects of neurodegeneration in older adults.</p><p>The hippocampus and hippocampal neuroplasticity are particularly affected by the</p><p>aging process. Age-related changes in the hippocampus, such as increased oxidative stress,</p><p>neuroinflammation, altered gene expression, hormone imbalance, reduced neurogenesis,</p><p>and impaired synaptic plasticity, have all been associated with cognitive decline [63].</p><p>Indeed, several studies have shown that aging is associated with decreased synaptic</p><p>plasticity, including LTP and LTD, which are thought to underlie learning and memory. For</p><p>example, hippocampal LTP was reduced in older adults, and this decrease was associated</p><p>with poorer memory performance [301]. Of note, the decline in hippocampal LTP observed</p><p>in aging rats was also shown to be associated with a decrease in the expression of estrogen</p><p>receptors in the hippocampus [302]. Furthermore, aged animals were shown to have</p><p>decreased synaptic plasticity in the projections from the entorhinal cortex to the dentate</p><p>gyrus [303] and reduced neuronal excitability of CA1 pyramidal neurons [304]. Conversely,</p><p>improving cyclic AMP response element-binding protein (CREB) signalizing enhanced</p><p>cognitive performance in aged animals [305].</p><p>In addition, aging has also been associated with a decline in structural plasticity</p><p>throughout the brain, including the hippocampus. Indeed, aging is associated with re-</p><p>duced dendritic arborization and length, spine density [306–308], as well as decreased</p><p>synaptogenesis (i.e., formation of new synapses) [299]. Furthermore, adult neurogenesis</p><p>also dramatically declines with age, with the proportion of neuronal stem cells that survive</p><p>to become mature neurons being significantly reduced in the aged brain [309,310]. Of</p><p>note, such decreases have been shown to impact learning strategies in aged mice [310].</p><p>In humans, neuroimaging studies have shown that aging is associated with a decrease</p><p>in gray matter volume and cortical thickness, which may reflect a reduction in synaptic</p><p>density [311].</p><p>In summary, the decline in neuroplasticity accompanying aging has important im-</p><p>plications for cognitive function and the risk of developing neurodegenerative diseases.</p><p>Understanding the mechanisms underlying the age-related decline in neuroplasticity is</p><p>crucial for developing strategies to promote healthy aging and reduce the risk of age-</p><p>related neurological disorders. To this end, non-invasive strategies aimed at improving</p><p>neuroplasticity, including physical exercise, cognitive stimulation, social engagement, and</p><p>dietary interventions, hold promise in halting the course of neurodegeneration in the aging</p><p>brain [162,215,312,313].</p><p>4.4. Non-Pharmacologic and Non-Invasive Strategies to Promote Neuroplasticity during Aging</p><p>As described above, molecular and structural changes within the brain with aging</p><p>can contribute to a decline in brain function and neurodegeneration [314]. However, the</p><p>cognitive reserve (i.e., the ability of the brain to cope with damage and deterioration)</p><p>can significantly reduce the risk of dementia and other age-related neurodegenerative</p><p>conditions. Various non-invasive and non-pharmacological approaches have been shown</p><p>to increase the cognitive reserve and potentially counteract the deleterious effects of aging</p><p>by protecting the brain against age-associated neurodegenerative processes [315]. These</p><p>strategies, including physical exercise, environmental enrichment and social stimulation, a</p><p>healthy diet, and caloric restriction, as well as sleep hygiene, have been shown to enhance</p><p>brain plasticity and improve cognitive function in aging individuals [316] while also</p><p>counteracting several age-induced alterations in brain signaling, structure, and function [63].</p><p>The following sections outline some of the non-invasive and non-pharmacological strategies</p><p>proposed to increase neuroplasticity in the aging brain.</p><p>Brain Sci. 2023, 13, 1610 17 of 32</p><p>4.4.1. Physical Exercise</p><p>Physical exercise is a well-established, non-invasive strategy for promoting neuroplas-</p><p>ticity during aging [317,318]. Exercise is known to increase the production of growth factors,</p><p>such as BDNF, which promote the survival and growth of neurons and synapses and play</p><p>a key role in neuroplasticity [319]. In addition, exercise has also been shown to increase the</p><p>expression of synapsin-I, a presynaptic protein related to motor performance [320].</p><p>Various studies have now shown the beneficial effects of exercise in maintaining cog-</p><p>nitive function in aging [162,318,321,322]. Indeed, physical exercise increased hippocampal</p><p>volume, improved spatial memory in older</p>