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The developing, aging neocortex: how genetics and epigenetics influence early developmental patterning and age-related change.

Huffman K - Front Genet (2012)

Bottom Line: During development, specification of neocortical tissue that leads to functional sensory and motor regions results from an interplay between cortically intrinsic, molecular processes, such as gene expression, and extrinsic processes regulated by sensory input.We posit that a role of neocortical gene expression in neocortex is to regulate plasticity mechanisms that impact critical periods for sensory and motor plasticity in aging.We describe how caloric restriction or reduction of oxidative stress may ameliorate effects of aging on the brain.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychology, University of California Riverside, CA, USA.

ABSTRACT
A hallmark of mammalian development is the generation of functional subdivisions within the nervous system. In humans, this regionalization creates a complex system that regulates behavior, cognition, memory, and emotion. During development, specification of neocortical tissue that leads to functional sensory and motor regions results from an interplay between cortically intrinsic, molecular processes, such as gene expression, and extrinsic processes regulated by sensory input. Cortical specification in mice occurs pre- and perinatally, when gene expression is robust and various anatomical distinctions are observed alongside an emergence of physiological function. After patterning, gene expression continues to shift and axonal connections mature into an adult form. The function of adult cortical gene expression may be to maintain neocortical subdivisions that were established during early patterning. As some changes in neocortical gene expression have been observed past early development into late adulthood, gene expression may also play a role in the altered neocortical function observed in age-related cognitive decline and brain dysfunction. This review provides a discussion of how neocortical gene expression and specific patterns of neocortical sensori-motor axonal connections develop and change throughout the lifespan of the animal. We posit that a role of neocortical gene expression in neocortex is to regulate plasticity mechanisms that impact critical periods for sensory and motor plasticity in aging. We describe results from several studies in aging brain that detail changes in gene expression that may relate to microstructural changes observed in brain anatomy. We discuss the role of altered glucocorticoid signaling in age-related cognitive and functional decline, as well as how aging in the brain may result from immune system activation. We describe how caloric restriction or reduction of oxidative stress may ameliorate effects of aging on the brain.

No MeSH data available.


Related in: MedlinePlus

Classic models of cortical patterning. Lateral view of cortical primordium at an early stage of neurogenesis (top row), and a later stage after thalamocortical axons have begun to enter the cortical plate when putative cortical sensory and motor areas are forming (bottom row). (Left) simplified protomap model. Early neocortex is patterned by predetermined molecular gradients across the developing cortex. Areal distinctions arise as specified by molecular determinants and these cortically intrinsic factors impart positional areal information. This is an activity-independent process. (Right) simplified protocortex model. Early neocortex is considered a blank slate, i.e., “tabula rasa.” Area differences arise based on sensory input from axons originating from the dorsal thalamus. Cortical cells and regions are “assigned” sensory and motor territories based on thalamic input. This is an activity-dependent process. m, putative motor cortex; s, putative somatosensory cortex, v, putative visual cortex; a, putative auditory cortex; VP, represents the ventral posterior nucleus of the dorsal thalamus which receives somatosensory input from receptors in the skin via brainstem nuclei; LGN, represents the lateral geniculate nucleus of the dorsal thalamus which receives visual input from the retina; MGN, represents the medial geniculate nucleus which receives auditory input from the cochlea.
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Figure 1: Classic models of cortical patterning. Lateral view of cortical primordium at an early stage of neurogenesis (top row), and a later stage after thalamocortical axons have begun to enter the cortical plate when putative cortical sensory and motor areas are forming (bottom row). (Left) simplified protomap model. Early neocortex is patterned by predetermined molecular gradients across the developing cortex. Areal distinctions arise as specified by molecular determinants and these cortically intrinsic factors impart positional areal information. This is an activity-independent process. (Right) simplified protocortex model. Early neocortex is considered a blank slate, i.e., “tabula rasa.” Area differences arise based on sensory input from axons originating from the dorsal thalamus. Cortical cells and regions are “assigned” sensory and motor territories based on thalamic input. This is an activity-dependent process. m, putative motor cortex; s, putative somatosensory cortex, v, putative visual cortex; a, putative auditory cortex; VP, represents the ventral posterior nucleus of the dorsal thalamus which receives somatosensory input from receptors in the skin via brainstem nuclei; LGN, represents the lateral geniculate nucleus of the dorsal thalamus which receives visual input from the retina; MGN, represents the medial geniculate nucleus which receives auditory input from the cochlea.

Mentions: All mammalian behavior is generated and regulated by the nervous system. In humans, neocortex is responsible for complex integration of information, the ability to utilize language, decision-making, motivation, and other high-level emotive-cognitive processes and behaviors. The complexity of neocortex emerges during development through a process called arealization, when specific sensory and motor functional areas are formed and connected to one another and to sub-cortical nuclei through a vast and complex network of intra- and extra-neocortical connections. Research on the developmental mechanisms that drive arealization has been influenced by two alternative hypotheses. Rakic (1988) famously detailed his Protomap hypothesis, suggesting that the fate of different neocortical regions were pre-specified in early development by yet-to-be characterized molecules within the proliferative zone, independent of input from the sensory systems (Figure 1, left). The notion that developing neocortex is patterned early in development, regardless of driven sensory input, with differential expression of genes during arealization is highly supported (Rakic, 1988; Miyashita-Lin et al., 1999; Nakagawa et al., 1999; Rubenstein et al., 1999; Bishop et al., 2000; Liu et al., 2000; Ragsdale and Grove, 2001; Zhou et al., 2001; Cecchi, 2002; Nakagawa and O’Leary, 2003; Funatsu et al., 2004; Sansom et al., 2005; Mallamaci and Stoykova, 2006; O’Leary and Sahara, 2008; Rakic et al., 2009; Bedogni et al., 2010). The alternate model, coined the Protocortex Hypothesis, emphasized the role of neural activity, via neocortically extrinsic thalamic sensory input, in determining neocortical areal fate (O’Leary, 1989; Figure 1, right). Based on our experimental finding in the neocortex of a blind mouse bilaterally enucleated at birth, we posit that both cortically intrinsic mechanisms, such as gene expression, and extrinsic mechanisms that involve input from the sensory organs via the dorsal thalamus interact to form the cortical map (Dye et al., 2012).


The developing, aging neocortex: how genetics and epigenetics influence early developmental patterning and age-related change.

Huffman K - Front Genet (2012)

Classic models of cortical patterning. Lateral view of cortical primordium at an early stage of neurogenesis (top row), and a later stage after thalamocortical axons have begun to enter the cortical plate when putative cortical sensory and motor areas are forming (bottom row). (Left) simplified protomap model. Early neocortex is patterned by predetermined molecular gradients across the developing cortex. Areal distinctions arise as specified by molecular determinants and these cortically intrinsic factors impart positional areal information. This is an activity-independent process. (Right) simplified protocortex model. Early neocortex is considered a blank slate, i.e., “tabula rasa.” Area differences arise based on sensory input from axons originating from the dorsal thalamus. Cortical cells and regions are “assigned” sensory and motor territories based on thalamic input. This is an activity-dependent process. m, putative motor cortex; s, putative somatosensory cortex, v, putative visual cortex; a, putative auditory cortex; VP, represents the ventral posterior nucleus of the dorsal thalamus which receives somatosensory input from receptors in the skin via brainstem nuclei; LGN, represents the lateral geniculate nucleus of the dorsal thalamus which receives visual input from the retina; MGN, represents the medial geniculate nucleus which receives auditory input from the cochlea.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3473232&req=5

Figure 1: Classic models of cortical patterning. Lateral view of cortical primordium at an early stage of neurogenesis (top row), and a later stage after thalamocortical axons have begun to enter the cortical plate when putative cortical sensory and motor areas are forming (bottom row). (Left) simplified protomap model. Early neocortex is patterned by predetermined molecular gradients across the developing cortex. Areal distinctions arise as specified by molecular determinants and these cortically intrinsic factors impart positional areal information. This is an activity-independent process. (Right) simplified protocortex model. Early neocortex is considered a blank slate, i.e., “tabula rasa.” Area differences arise based on sensory input from axons originating from the dorsal thalamus. Cortical cells and regions are “assigned” sensory and motor territories based on thalamic input. This is an activity-dependent process. m, putative motor cortex; s, putative somatosensory cortex, v, putative visual cortex; a, putative auditory cortex; VP, represents the ventral posterior nucleus of the dorsal thalamus which receives somatosensory input from receptors in the skin via brainstem nuclei; LGN, represents the lateral geniculate nucleus of the dorsal thalamus which receives visual input from the retina; MGN, represents the medial geniculate nucleus which receives auditory input from the cochlea.
Mentions: All mammalian behavior is generated and regulated by the nervous system. In humans, neocortex is responsible for complex integration of information, the ability to utilize language, decision-making, motivation, and other high-level emotive-cognitive processes and behaviors. The complexity of neocortex emerges during development through a process called arealization, when specific sensory and motor functional areas are formed and connected to one another and to sub-cortical nuclei through a vast and complex network of intra- and extra-neocortical connections. Research on the developmental mechanisms that drive arealization has been influenced by two alternative hypotheses. Rakic (1988) famously detailed his Protomap hypothesis, suggesting that the fate of different neocortical regions were pre-specified in early development by yet-to-be characterized molecules within the proliferative zone, independent of input from the sensory systems (Figure 1, left). The notion that developing neocortex is patterned early in development, regardless of driven sensory input, with differential expression of genes during arealization is highly supported (Rakic, 1988; Miyashita-Lin et al., 1999; Nakagawa et al., 1999; Rubenstein et al., 1999; Bishop et al., 2000; Liu et al., 2000; Ragsdale and Grove, 2001; Zhou et al., 2001; Cecchi, 2002; Nakagawa and O’Leary, 2003; Funatsu et al., 2004; Sansom et al., 2005; Mallamaci and Stoykova, 2006; O’Leary and Sahara, 2008; Rakic et al., 2009; Bedogni et al., 2010). The alternate model, coined the Protocortex Hypothesis, emphasized the role of neural activity, via neocortically extrinsic thalamic sensory input, in determining neocortical areal fate (O’Leary, 1989; Figure 1, right). Based on our experimental finding in the neocortex of a blind mouse bilaterally enucleated at birth, we posit that both cortically intrinsic mechanisms, such as gene expression, and extrinsic mechanisms that involve input from the sensory organs via the dorsal thalamus interact to form the cortical map (Dye et al., 2012).

Bottom Line: During development, specification of neocortical tissue that leads to functional sensory and motor regions results from an interplay between cortically intrinsic, molecular processes, such as gene expression, and extrinsic processes regulated by sensory input.We posit that a role of neocortical gene expression in neocortex is to regulate plasticity mechanisms that impact critical periods for sensory and motor plasticity in aging.We describe how caloric restriction or reduction of oxidative stress may ameliorate effects of aging on the brain.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychology, University of California Riverside, CA, USA.

ABSTRACT
A hallmark of mammalian development is the generation of functional subdivisions within the nervous system. In humans, this regionalization creates a complex system that regulates behavior, cognition, memory, and emotion. During development, specification of neocortical tissue that leads to functional sensory and motor regions results from an interplay between cortically intrinsic, molecular processes, such as gene expression, and extrinsic processes regulated by sensory input. Cortical specification in mice occurs pre- and perinatally, when gene expression is robust and various anatomical distinctions are observed alongside an emergence of physiological function. After patterning, gene expression continues to shift and axonal connections mature into an adult form. The function of adult cortical gene expression may be to maintain neocortical subdivisions that were established during early patterning. As some changes in neocortical gene expression have been observed past early development into late adulthood, gene expression may also play a role in the altered neocortical function observed in age-related cognitive decline and brain dysfunction. This review provides a discussion of how neocortical gene expression and specific patterns of neocortical sensori-motor axonal connections develop and change throughout the lifespan of the animal. We posit that a role of neocortical gene expression in neocortex is to regulate plasticity mechanisms that impact critical periods for sensory and motor plasticity in aging. We describe results from several studies in aging brain that detail changes in gene expression that may relate to microstructural changes observed in brain anatomy. We discuss the role of altered glucocorticoid signaling in age-related cognitive and functional decline, as well as how aging in the brain may result from immune system activation. We describe how caloric restriction or reduction of oxidative stress may ameliorate effects of aging on the brain.

No MeSH data available.


Related in: MedlinePlus