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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

Intra-neocortical projection patterns in P0 mice with rostral patterning defects (Fgf8neo/neo mutants) compared with P0 control littermates (Fgf8+/+). Hundred micrometer coronal sections presented in rostral to caudal series of brain hemispheres following DiI [red asterisk, (A,A′)] or DiA [green asterisk, (D,D′)] crystal placement the rostral and caudal neocortex (putative somatosensory and visual cortex, respectively), oriented with dorsal up and lateral to the right. Sections were analyzed for the distributions of retrogradely labeled cell bodies, with lateral view reconstructions shown in (F,F′). Hemi-sections from control mice (A–E) demonstrate no overlap of retrograde label from dye placements in putative somatosensory (A) or visual (D) cortex, as red and green label remain segregated. However, Fgf8neo/neo mutants showed a robust phenotype, indicated by red–green overlap [yellow label, (B′–D′)] and red label caudal to this overlap (E′) reflecting ectopic caudal projections to rostral somatosensory cortical locations. The ectopic intra-neocortical connections are easily observed in the reconstructions where caudal locations aberrantly project to rostral fields in the mutant (F′) but not in the control (F). (F,F′)-Rostral is left, dorsal up. Figure adapted from Huffman et al. (2004).
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Figure 3: Intra-neocortical projection patterns in P0 mice with rostral patterning defects (Fgf8neo/neo mutants) compared with P0 control littermates (Fgf8+/+). Hundred micrometer coronal sections presented in rostral to caudal series of brain hemispheres following DiI [red asterisk, (A,A′)] or DiA [green asterisk, (D,D′)] crystal placement the rostral and caudal neocortex (putative somatosensory and visual cortex, respectively), oriented with dorsal up and lateral to the right. Sections were analyzed for the distributions of retrogradely labeled cell bodies, with lateral view reconstructions shown in (F,F′). Hemi-sections from control mice (A–E) demonstrate no overlap of retrograde label from dye placements in putative somatosensory (A) or visual (D) cortex, as red and green label remain segregated. However, Fgf8neo/neo mutants showed a robust phenotype, indicated by red–green overlap [yellow label, (B′–D′)] and red label caudal to this overlap (E′) reflecting ectopic caudal projections to rostral somatosensory cortical locations. The ectopic intra-neocortical connections are easily observed in the reconstructions where caudal locations aberrantly project to rostral fields in the mutant (F′) but not in the control (F). (F,F′)-Rostral is left, dorsal up. Figure adapted from Huffman et al. (2004).

Mentions: Mice with altered FGF function in the brain have disrupted cortical arealization, further supporting the Protomap hypothesis (Fukuchi-Shimogori and Grove, 2003; Garel et al., 2003; Huffman et al., 2004; Cholfin and Rubenstein, 2008, Iwata and Hevner, 2009). Cortical gene expression patterns are disrupted in mutant mice with reduced FGF8 signaling. Specifically, a reduction in Fgf8 expression at the rostral pole of the neocortex leads to a rostral shift of both RZRβ and Id2 expression (Figure 2, arrows). This disruption in normal genetic patterning is correlated with ectopic ipsilateral sensory INCs in the mutant (Figure 3). Caudal neurons send projections to far rostral locations, perhaps following the shift in gene gradients (Figures 2 and 3; Garel et al., 2003; Huffman et al., 2004). Results from these studies and others have demonstrated that Fgf8 plays a regulatory role in the development of intra-neocortical connectivity and led our laboratory to further investigate gene expression-INC relationships (Fukuchi-Shimogori and Grove, 2001, 2003; Garel et al., 2003; Huffman et al., 2004; Shimogori and Grove, 2005; Dye et al., 2011a,b). We have examined the gene expression patterns of seven regulatory genes that are expressed in specific regions or gradients across the cortical sheet in early development (Miyashita-Lin et al., 1999; Garel et al., 2003; Huffman et al., 2004; Sur and Rubenstein, 2005) from the embryonic period to adulthood in mouse and studied their relationship to INC development. These genes, which are showcased in two recent reports (Dye et al., 2011a,b), are believed to be involved in the process of area and areal boundary formation as expression patterns often correlate with emergence of area borders in development (Dye et al., 2011a). The seven genes included in the analyses were COUP-TFI, Id2, RZRβ, Cadherin 8, Ephrin A5, Eph A7, and Lhx2 (Dye et al., 2011a,b), some of which are shown in this review.


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

Huffman K - Front Genet (2012)

Intra-neocortical projection patterns in P0 mice with rostral patterning defects (Fgf8neo/neo mutants) compared with P0 control littermates (Fgf8+/+). Hundred micrometer coronal sections presented in rostral to caudal series of brain hemispheres following DiI [red asterisk, (A,A′)] or DiA [green asterisk, (D,D′)] crystal placement the rostral and caudal neocortex (putative somatosensory and visual cortex, respectively), oriented with dorsal up and lateral to the right. Sections were analyzed for the distributions of retrogradely labeled cell bodies, with lateral view reconstructions shown in (F,F′). Hemi-sections from control mice (A–E) demonstrate no overlap of retrograde label from dye placements in putative somatosensory (A) or visual (D) cortex, as red and green label remain segregated. However, Fgf8neo/neo mutants showed a robust phenotype, indicated by red–green overlap [yellow label, (B′–D′)] and red label caudal to this overlap (E′) reflecting ectopic caudal projections to rostral somatosensory cortical locations. The ectopic intra-neocortical connections are easily observed in the reconstructions where caudal locations aberrantly project to rostral fields in the mutant (F′) but not in the control (F). (F,F′)-Rostral is left, dorsal up. Figure adapted from Huffman et al. (2004).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Intra-neocortical projection patterns in P0 mice with rostral patterning defects (Fgf8neo/neo mutants) compared with P0 control littermates (Fgf8+/+). Hundred micrometer coronal sections presented in rostral to caudal series of brain hemispheres following DiI [red asterisk, (A,A′)] or DiA [green asterisk, (D,D′)] crystal placement the rostral and caudal neocortex (putative somatosensory and visual cortex, respectively), oriented with dorsal up and lateral to the right. Sections were analyzed for the distributions of retrogradely labeled cell bodies, with lateral view reconstructions shown in (F,F′). Hemi-sections from control mice (A–E) demonstrate no overlap of retrograde label from dye placements in putative somatosensory (A) or visual (D) cortex, as red and green label remain segregated. However, Fgf8neo/neo mutants showed a robust phenotype, indicated by red–green overlap [yellow label, (B′–D′)] and red label caudal to this overlap (E′) reflecting ectopic caudal projections to rostral somatosensory cortical locations. The ectopic intra-neocortical connections are easily observed in the reconstructions where caudal locations aberrantly project to rostral fields in the mutant (F′) but not in the control (F). (F,F′)-Rostral is left, dorsal up. Figure adapted from Huffman et al. (2004).
Mentions: Mice with altered FGF function in the brain have disrupted cortical arealization, further supporting the Protomap hypothesis (Fukuchi-Shimogori and Grove, 2003; Garel et al., 2003; Huffman et al., 2004; Cholfin and Rubenstein, 2008, Iwata and Hevner, 2009). Cortical gene expression patterns are disrupted in mutant mice with reduced FGF8 signaling. Specifically, a reduction in Fgf8 expression at the rostral pole of the neocortex leads to a rostral shift of both RZRβ and Id2 expression (Figure 2, arrows). This disruption in normal genetic patterning is correlated with ectopic ipsilateral sensory INCs in the mutant (Figure 3). Caudal neurons send projections to far rostral locations, perhaps following the shift in gene gradients (Figures 2 and 3; Garel et al., 2003; Huffman et al., 2004). Results from these studies and others have demonstrated that Fgf8 plays a regulatory role in the development of intra-neocortical connectivity and led our laboratory to further investigate gene expression-INC relationships (Fukuchi-Shimogori and Grove, 2001, 2003; Garel et al., 2003; Huffman et al., 2004; Shimogori and Grove, 2005; Dye et al., 2011a,b). We have examined the gene expression patterns of seven regulatory genes that are expressed in specific regions or gradients across the cortical sheet in early development (Miyashita-Lin et al., 1999; Garel et al., 2003; Huffman et al., 2004; Sur and Rubenstein, 2005) from the embryonic period to adulthood in mouse and studied their relationship to INC development. These genes, which are showcased in two recent reports (Dye et al., 2011a,b), are believed to be involved in the process of area and areal boundary formation as expression patterns often correlate with emergence of area borders in development (Dye et al., 2011a). The seven genes included in the analyses were COUP-TFI, Id2, RZRβ, Cadherin 8, Ephrin A5, Eph A7, and Lhx2 (Dye et al., 2011a,b), some of which are shown in this review.

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