Adolescence involves significant reorganization within the medial prefrontal cortex (mPFC), inclu... more Adolescence involves significant reorganization within the medial prefrontal cortex (mPFC), including modifications to inhibitory neurotransmission mediated through parvalbumin interneurons (PV) and their surrounding perineuronal nets (PNNs). These developmental changes, which result in increased PV neuron activity in adulthood, may be disrupted by drug use and cause lasting changes in mPFC function and behavior. Methamphetamine (METH), which is a readily available drug used by some adolescents, increases PV neuron activity and could influence the activity-dependent maturational process of these neurons. In the present study, we used male and female Sprague Dawley rats to test the hypothesis that METH exposure influences PV and PNN expression in a sex- and age-specific manner. Rats were injected daily with saline or 3.0 mg/kg METH from early adolescence (EA; 30-38 days old), late adolescence (LA; 40-48 days old), or young adulthood (60-68 days old). One day following exposure, effec...
During aging, rats of both sexes experience a decline in performance on hippocampal-dependent tas... more During aging, rats of both sexes experience a decline in performance on hippocampal-dependent tasks. Investigations into the neuroanatomical correlates of this functional decline have been conducted almost exclusively in male subjects. In the present study, dendritic spine density in stratum radiatum and complexity of the entire apical dendritic tree were quantified using Golgi-Cox-stained tissue in young (3-5 months) and aged (19-22 months) rats of both sexes. Because both cognitive decline and hippocampal morphology may be influenced by ovarian hormonal state, young adult females were examined during either proestrus or estrus, and aged females were examined in one of two reproductively senescent states: persistent estrus or persistent diestrus. A sex difference in dendritic branching of CA1 pyramidal cells was found among young adults. However, this difference disappeared during aging, due to a reduction in branching with age for males but not for females. Spine density was not influenced by age or sex, nor did ovarian hormone status influence either measure. These results are consistent with our previous findings in the rat medial prefrontal cortex and primary motor cortex and with the human literature, which indicate that age-related atrophy of cognitive brain regions is more severe for males than females.
The prefrontal cortex (PFC) is a late developing region of the cortex, and its protracted maturat... more The prefrontal cortex (PFC) is a late developing region of the cortex, and its protracted maturation during adolescence may confer a period of plasticity. Closure of critical, or sensitive, periods in sensory cortices coincides with perineuronal net (PNN) expression, leading to enhanced inhibitory function and synaptic stabilization. PNN density has been found to increase across adolescence in the male rat medial PFC (mPFC). Here, we examined both male and female rats at four time points spanning adolescent development to stereologically quantify the number and intensity of PNNs in the mPFC. Additionally, because puberty coincides with broad behavioral and neuroanatomical changes, we collected tissue from age-matched pre-and post-pubertal siblings within a litter. Results indicate that both males and females show an increase in the total number and intensity of mPFC PNNs between postnatal day (P) 30 and P60. As we have previously found, white matter under the mPFC also increased at the same time. Male puberty did not affect PNNs, while female pubertal onset led to an abrupt decrease in the total number of PNNs that persisted through mid-adolescence before increasing at P60. Despite the change in PNN number, the intensity of female PNNs was not affected by puberty. Thus, though males and females show increases in mPFC PNNs during adolescence, the pubertal decrease in the number of PNNs in Terms of use and reuse: academic research for non-commercial purposes, see here for full terms. https://www.springer.com/aamterms-v1
bioRxiv (Cold Spring Harbor Laboratory), Mar 31, 2021
In female rats, pubertal onset is associated with maturation of the medial prefrontal cortex (mPF... more In female rats, pubertal onset is associated with maturation of the medial prefrontal cortex (mPFC) and mPFC-mediated behaviors. These behavioral and anatomical changes are likely due to effects of estrogen at the nuclear estrogen receptor beta (ERβ), which is expressed at higher levels than the estrogen receptor alpha (ERα) isoform in the adult mPFC. Researchers have previously quantified ERβ protein and Esr2 RNA in rodents during early postnatal development and adulthood, but an adolescent-specific trajectory of this receptor in the mPFC has not been
Hormones influence neurodevelopment which can result in vulnerability to endocrine disruptors suc... more Hormones influence neurodevelopment which can result in vulnerability to endocrine disruptors such as phthalates during both the perinatal period and adolescence. Using a rat model, we have previously shown that perinatal exposure to an environmentally relevant phthalate mixture at low doses results in cognitive flexibility deficits in adults and a reduction in neuron and synapse number within the medial prefrontal cortex. Here, we further examined the behavioral effects of exposure to an environmentally relevant mixture of phthalates at low doses during either perinatal development or adolescence. Using the elevated plus maze, adult females, not males, exposed to phthalates during adolescence showed indications of reduced anxiety-like behavior while perinatal exposed animals were unaffected. There was no effect of adolescent phthalate exposure on cognitive flexibility using the attentional set shift paradigm in either sex, unlike the impairments we have previously reported following perinatal exposure (Kougias et al., 2018b). Finally, there was no effect of phthalate exposure during either time frame on sensorimotor gating measured using prepulse inhibition. Environmentally relevant phthalate exposure during the perinatal period or during adolescence did not induce widespread changes in the adult behaviors measured here.
Rats reared from weaning in a complex environment with other rats and numerous objects display se... more Rats reared from weaning in a complex environment with other rats and numerous objects display sex differences in several brain areas, yet there is little systematic information on the types of interactions that rats have within complex environments or whether there are sex differences in these interactions. Therefore, male and female rats were observed in the complex environment over a 15-30-day period in three separate replications that included same-sex and mixed sex groups of rats. The rats spent considerably more time interacting with the objects than in social interactions in all replications, and the types of interactions varied little over the length of the study. A few sex differences appeared, such as in play fighting, but these differences were small and not consistent across replications. Male and female rats interacted with the environment in a very similar manner.
The prefrontal cortex continues to develop throughout adolescence in several species, and our lab... more The prefrontal cortex continues to develop throughout adolescence in several species, and our laboratory has demonstrated that during adolescence there is a decrease in neurons in the rat medial prefrontal cortex (mPFC). A PFC-dependent task, the delayed alternation task, was used in the present study to examine the function of the mPFC while it is still maturing in rats of both sexes. A deficit was found in adolescents when compared to adults during 15-and 60-s delays but not at other delays (5, 10, 30, and 90 s). Furthermore, adolescents committed more perseverative errors. No significant sex differences occurred at any delay for either age group; however, in the no delay training sessions, adolescent males reached criterion faster than females. These results indicate that performance on a mPFC-dependent task improves between adolescence and adulthood.
There is recent evidence of continuing development throughout adolescence in two neural areas inv... more There is recent evidence of continuing development throughout adolescence in two neural areas involved in emotion and cognition, the basolateral amygdala (BLN) and the medial prefrontal cortex (mPFC). Previous research from our laboratory has demonstrated a cellular loss in both of these brain regions in rats between postnatal day (P) 35 and 90. This study investigates dendritic changes in pyramidal neurons of the BLN and Layer 5 of the mPFC at P20 (juvenile), 35 (puberty), and 90 (adulthood) in hooded rats of both sexes. Dendritic branching and dendritic spines were quantified in Golgi-Cox impregnated tissue. Between P20 and 35, dendritic length and complexity, as well as the density of dendritic spines, increased in both structures. Between P35 and 90, dendritic spines in the mPFC neurons significantly decreased in both sexes, while a loss of basilar dendrites was only detected in females. In the BLN, there was an increase in the number of branches between P35 and 90 without an increase in the total length of the dendritic tree. BLN spine density also remained stable during this period. These results show that the dendritic tree grows prior to puberty while dendritic remodeling and pruning occurs after puberty in both of these neural areas. This late development may lead to susceptibilities to psychopathologies and addictions that often develop at this time. Synapse
This review is centered on anatomical sex differences in neuronal organization in parts of the ra... more This review is centered on anatomical sex differences in neuronal organization in parts of the rat nervous system that are associated with "cognitive" rather than reproductive function: the hippocampus and the cerebral cortex, including the corpus callosum. All three of these structures exhibit sexual dimorphism at the cellular level. It is notable that there is a dissociation between the gross size of a structure and the underlying cellular dimorphism. For example, no sex differences were detected in the size of the splenium of the corpus callosum, but female rats had more axons in this area than did male rats. These "cognitive" regions of the brain are susceptible to the nature of the postweaning environment; the degree and even direction of sex differences was influenced by the environment. There is evidence that testosterone plays a role in the dimorphism of the hippocampus.
A contested report of sex differences in the size of the splenium of the corpus callosum in human... more A contested report of sex differences in the size of the splenium of the corpus callosum in humans prompted the present examination of the corpus callosum in the rat. We have previously found that sex differences can vary with the rearing environment. Consequently, male and female rats were raised from weaning to 55 days of age in either a complex or an isolated environment. There were no sex differences in the size of the corpus callosum in sagittal cross section in these rats; however, rats of both sexes had a larger posterior third of the corpus callosum if they were raised in the complex environment. Because the corpus callosum continues to grow in size past 55 days of age, we examined socially housed rats at 113 days and again found no sex differences. The splenium was examined with electron microscopy in complex and isolation reared rats at 55 days of age. The ultrastructural analysis revealed differences that were not apparent from gross size measures. Females had more unmyelinated axons regardless of environment, and females from the complex environment had more myelinated axons than comparably housed males. In contrast, males in the complex environment had larger myelinated axons than females. Rats of both sexes from the complex environment had larger and more unmyelinated axons than isolated rats. In addition in myelinated axons, plasticity in the females occurred through changes in axon number and in males, through axon size. Thus sex differences exist in axonal number and size and the environment influences these differences.
Previous studies have shown that the number of dendritic spines and synapses in hippocampal CA1 s... more Previous studies have shown that the number of dendritic spines and synapses in hippocampal CA1 stratum radiatum decreases more than 30% between the proestrus (high estrogen) and estrus (low estrogen) phases of the rat estrous cycle [10,27]. In the present study, we investigated whether hippocampal synaptic plasticity, as measured by long-term potentiation (LTP), might also vary across the estrous cycle of the female rat. Male rats, and female rats at each phase of the estrous cycle were tested in either the morning or afternoon. There were no significant group differences in the pre-LTP I/0 curves. However, females examined during the afternoon of proestrus, the phase during which prior studies indicate synapse number to be highest, demonstrated the greatest degree of potentiation. Diestrus, proestrus and estrus females tested in the morning demonstrated similar amounts of potentiation. There were also significant differences in post-LTP I/0 curves between the afternoon proestrus females and males tested in the afternoon. These results suggest that gonadal hormones, interacting with the time of day, may regulate neural processes underlying learning and memory.
An earlier report from our laboratory demonstrated that there were sex differences in the dendrit... more An earlier report from our laboratory demonstrated that there were sex differences in the dendritic tree of granule neurons from the rat dentate gyrus (Juraska, Fitch, Henderson, & Rivers, 1985). To investigate the hormonal basis for these sex differences, we castrated or sham-operated male rats within hours of birth. At weaning, rats from both hormonal groups were assigned to either a complex or an isolated environment. After 1 month in the differential environments, the rats' brains were stained with Golgi-Cox, and the dendritic fields of granule neurons were quantified from 28 animals. Castrated males showed a response to the environments (complex > isolated) that was similar to that ofnormal females from previous work. This plasticity did not occur in the sham-operated males. However, the castrated males had fewer dendrites than did sham-operated males overall, so that there were no differences between the sham-operated and castrated males in the complex environment, where sex differences (female > male) had been previously found. Therefore, males that were neonatally castrated partially mirrored females in their pattern of dendritic sex differences in dentate granule neurons.
Adolescents and females experience worse outcomes of drug use compared to adults and males. This ... more Adolescents and females experience worse outcomes of drug use compared to adults and males. This could result from age-and sex-specific consequences of drug exposure on brain function and cognitive behavior. In the current study, we examined whether a history of intravenous methamphetamine (METH) self-administration impacted cognitive flexibility and 5-HT 2C R localization in the orbitofrontal cortex (OFC) in an age-and sex-dependent manner. Strategy shifting was assessed in male and female Sprague-Dawley rats that had self-administered METH (0.08 mg/kg/inf) or received non-contingent infusions of saline during periadolescence or young adulthood. After all rats reached adulthood, they were tested in an operant strategy shifting task and their brains were subsequently analyzed using immunofluorescence to quantify co-localization of 5-HT 2C receptors with parvalbumin interneurons in the OFC. We found that adolescent-onset females were the only group impaired during discrimination and reversal learning, but they did not exhibit changes in localization of 5-HT 2C receptors. In contrast, adult-onset males exhibited a significant increase in co-localization of 5-HT 2C receptors within parvalbumin interneurons in the left hemisphere of the OFC. These studies reveal that age and sex differences in drug-induced deficits in reversal learning and 5-HT 2C R co-localization with parvalbumin interneurons are dissociable and can manifest independently. In addition, these data highlight the potential for certain treatment approaches to be more suitable in some populations compared to others, such as alleviating drug-induced cognitive deficits as a focus for treatment in adolescent females.
The growth and organization of the developing brain are known to be influenced by hormones, but l... more The growth and organization of the developing brain are known to be influenced by hormones, but little is known about whether disruption of hormones affects cortical regions, such as mPFC. This region is particularly important given its involvement in executive functions and implication in the pathology of many neuropsychiatric disorders. Here, we examine the long-term effects of perinatal exposure to endocrine-disrupting compounds, the phthalates, on the mPFC and associated behavior. This investigation is pertinent as humans are ubiquitously exposed to phthalates through a variety of consumer products and phthalates can readily cross the placenta and be delivered to offspring via lactation. Pregnant dams orally consumed an environmentally relevant mixture of phthalates at 0, 200, or 1000 g/kg/d through pregnancy and for 10 d while lactating. As adults, offspring were tested in an attentional set-shifting task, which assesses cognitive flexibility. Brains were also examined in adulthood for stereological quantification of the number of neurons, glia, and synapses within the mPFC. We found that, independent of sex, perinatal phthalate exposure at either dose resulted in a reduction in neuron number, synapse number, and size of the mPFC and a deficit in cognitive flexibility. Interestingly, the number of synapses was correlated with cognitive flexibility, such that rats with fewer synapses were less cognitively flexible than those with more synapses. These results demonstrate that perinatal phthalate exposure can have long-term effects on the cortex and behavior of both male and female rats.
The expression of several inflammatory cytokines that inhibit synaptic plasticity and hippocampal... more The expression of several inflammatory cytokines that inhibit synaptic plasticity and hippocampal-dependent learning and memory is higher in the brains of aged mice compared to young adults after peripheral injection of lipopolysaccharide (LPS). In this study we investigated whether the exaggerated inflammatory cytokine response in the hippocampus of aged mice after IP injection of LPS is associated with architectural changes to dendrites of pyramidal neurons in the dorsal CA1 hippocampus. Compared to young adults, aged mice had higher basal expression of MHC class II, lower basal expression of two neurotrophins, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), and a decrease in total dendritic length in both the basal and apical tree. After IP LPS administration, expression of IL-1beta, IL-6, and TNFalpha mRNA was higher in hippocampus of aged mice compared to young adults whereas NGF and BDNF mRNA was reduced similarly in both age groups. The basal dendritic tree was not affected by LPS in either adult or aged mice 72h after treatment; however, length and branching of the apical tree was reduced by LPS in aged but not adult mice. The present findings indicate that a peripheral infection in the aged can cause a heightened inflammatory cytokine response in the hippocampus and atrophy of hippocampal neurons. Architectural changes to dorsal CA1 hippocampal neurons may contribute to cognitive disorders evident in elderly patients with an infection.
Adolescence involves significant reorganization within the medial prefrontal cortex (mPFC), inclu... more Adolescence involves significant reorganization within the medial prefrontal cortex (mPFC), including modifications to inhibitory neurotransmission mediated through parvalbumin interneurons (PV) and their surrounding perineuronal nets (PNNs). These developmental changes, which result in increased PV neuron activity in adulthood, may be disrupted by drug use and cause lasting changes in mPFC function and behavior. Methamphetamine (METH), which is a readily available drug used by some adolescents, increases PV neuron activity and could influence the activity-dependent maturational process of these neurons. In the present study, we used male and female Sprague Dawley rats to test the hypothesis that METH exposure influences PV and PNN expression in a sex- and age-specific manner. Rats were injected daily with saline or 3.0 mg/kg METH from early adolescence (EA; 30-38 days old), late adolescence (LA; 40-48 days old), or young adulthood (60-68 days old). One day following exposure, effec...
During aging, rats of both sexes experience a decline in performance on hippocampal-dependent tas... more During aging, rats of both sexes experience a decline in performance on hippocampal-dependent tasks. Investigations into the neuroanatomical correlates of this functional decline have been conducted almost exclusively in male subjects. In the present study, dendritic spine density in stratum radiatum and complexity of the entire apical dendritic tree were quantified using Golgi-Cox-stained tissue in young (3-5 months) and aged (19-22 months) rats of both sexes. Because both cognitive decline and hippocampal morphology may be influenced by ovarian hormonal state, young adult females were examined during either proestrus or estrus, and aged females were examined in one of two reproductively senescent states: persistent estrus or persistent diestrus. A sex difference in dendritic branching of CA1 pyramidal cells was found among young adults. However, this difference disappeared during aging, due to a reduction in branching with age for males but not for females. Spine density was not influenced by age or sex, nor did ovarian hormone status influence either measure. These results are consistent with our previous findings in the rat medial prefrontal cortex and primary motor cortex and with the human literature, which indicate that age-related atrophy of cognitive brain regions is more severe for males than females.
The prefrontal cortex (PFC) is a late developing region of the cortex, and its protracted maturat... more The prefrontal cortex (PFC) is a late developing region of the cortex, and its protracted maturation during adolescence may confer a period of plasticity. Closure of critical, or sensitive, periods in sensory cortices coincides with perineuronal net (PNN) expression, leading to enhanced inhibitory function and synaptic stabilization. PNN density has been found to increase across adolescence in the male rat medial PFC (mPFC). Here, we examined both male and female rats at four time points spanning adolescent development to stereologically quantify the number and intensity of PNNs in the mPFC. Additionally, because puberty coincides with broad behavioral and neuroanatomical changes, we collected tissue from age-matched pre-and post-pubertal siblings within a litter. Results indicate that both males and females show an increase in the total number and intensity of mPFC PNNs between postnatal day (P) 30 and P60. As we have previously found, white matter under the mPFC also increased at the same time. Male puberty did not affect PNNs, while female pubertal onset led to an abrupt decrease in the total number of PNNs that persisted through mid-adolescence before increasing at P60. Despite the change in PNN number, the intensity of female PNNs was not affected by puberty. Thus, though males and females show increases in mPFC PNNs during adolescence, the pubertal decrease in the number of PNNs in Terms of use and reuse: academic research for non-commercial purposes, see here for full terms. https://www.springer.com/aamterms-v1
bioRxiv (Cold Spring Harbor Laboratory), Mar 31, 2021
In female rats, pubertal onset is associated with maturation of the medial prefrontal cortex (mPF... more In female rats, pubertal onset is associated with maturation of the medial prefrontal cortex (mPFC) and mPFC-mediated behaviors. These behavioral and anatomical changes are likely due to effects of estrogen at the nuclear estrogen receptor beta (ERβ), which is expressed at higher levels than the estrogen receptor alpha (ERα) isoform in the adult mPFC. Researchers have previously quantified ERβ protein and Esr2 RNA in rodents during early postnatal development and adulthood, but an adolescent-specific trajectory of this receptor in the mPFC has not been
Hormones influence neurodevelopment which can result in vulnerability to endocrine disruptors suc... more Hormones influence neurodevelopment which can result in vulnerability to endocrine disruptors such as phthalates during both the perinatal period and adolescence. Using a rat model, we have previously shown that perinatal exposure to an environmentally relevant phthalate mixture at low doses results in cognitive flexibility deficits in adults and a reduction in neuron and synapse number within the medial prefrontal cortex. Here, we further examined the behavioral effects of exposure to an environmentally relevant mixture of phthalates at low doses during either perinatal development or adolescence. Using the elevated plus maze, adult females, not males, exposed to phthalates during adolescence showed indications of reduced anxiety-like behavior while perinatal exposed animals were unaffected. There was no effect of adolescent phthalate exposure on cognitive flexibility using the attentional set shift paradigm in either sex, unlike the impairments we have previously reported following perinatal exposure (Kougias et al., 2018b). Finally, there was no effect of phthalate exposure during either time frame on sensorimotor gating measured using prepulse inhibition. Environmentally relevant phthalate exposure during the perinatal period or during adolescence did not induce widespread changes in the adult behaviors measured here.
Rats reared from weaning in a complex environment with other rats and numerous objects display se... more Rats reared from weaning in a complex environment with other rats and numerous objects display sex differences in several brain areas, yet there is little systematic information on the types of interactions that rats have within complex environments or whether there are sex differences in these interactions. Therefore, male and female rats were observed in the complex environment over a 15-30-day period in three separate replications that included same-sex and mixed sex groups of rats. The rats spent considerably more time interacting with the objects than in social interactions in all replications, and the types of interactions varied little over the length of the study. A few sex differences appeared, such as in play fighting, but these differences were small and not consistent across replications. Male and female rats interacted with the environment in a very similar manner.
The prefrontal cortex continues to develop throughout adolescence in several species, and our lab... more The prefrontal cortex continues to develop throughout adolescence in several species, and our laboratory has demonstrated that during adolescence there is a decrease in neurons in the rat medial prefrontal cortex (mPFC). A PFC-dependent task, the delayed alternation task, was used in the present study to examine the function of the mPFC while it is still maturing in rats of both sexes. A deficit was found in adolescents when compared to adults during 15-and 60-s delays but not at other delays (5, 10, 30, and 90 s). Furthermore, adolescents committed more perseverative errors. No significant sex differences occurred at any delay for either age group; however, in the no delay training sessions, adolescent males reached criterion faster than females. These results indicate that performance on a mPFC-dependent task improves between adolescence and adulthood.
There is recent evidence of continuing development throughout adolescence in two neural areas inv... more There is recent evidence of continuing development throughout adolescence in two neural areas involved in emotion and cognition, the basolateral amygdala (BLN) and the medial prefrontal cortex (mPFC). Previous research from our laboratory has demonstrated a cellular loss in both of these brain regions in rats between postnatal day (P) 35 and 90. This study investigates dendritic changes in pyramidal neurons of the BLN and Layer 5 of the mPFC at P20 (juvenile), 35 (puberty), and 90 (adulthood) in hooded rats of both sexes. Dendritic branching and dendritic spines were quantified in Golgi-Cox impregnated tissue. Between P20 and 35, dendritic length and complexity, as well as the density of dendritic spines, increased in both structures. Between P35 and 90, dendritic spines in the mPFC neurons significantly decreased in both sexes, while a loss of basilar dendrites was only detected in females. In the BLN, there was an increase in the number of branches between P35 and 90 without an increase in the total length of the dendritic tree. BLN spine density also remained stable during this period. These results show that the dendritic tree grows prior to puberty while dendritic remodeling and pruning occurs after puberty in both of these neural areas. This late development may lead to susceptibilities to psychopathologies and addictions that often develop at this time. Synapse
This review is centered on anatomical sex differences in neuronal organization in parts of the ra... more This review is centered on anatomical sex differences in neuronal organization in parts of the rat nervous system that are associated with "cognitive" rather than reproductive function: the hippocampus and the cerebral cortex, including the corpus callosum. All three of these structures exhibit sexual dimorphism at the cellular level. It is notable that there is a dissociation between the gross size of a structure and the underlying cellular dimorphism. For example, no sex differences were detected in the size of the splenium of the corpus callosum, but female rats had more axons in this area than did male rats. These "cognitive" regions of the brain are susceptible to the nature of the postweaning environment; the degree and even direction of sex differences was influenced by the environment. There is evidence that testosterone plays a role in the dimorphism of the hippocampus.
A contested report of sex differences in the size of the splenium of the corpus callosum in human... more A contested report of sex differences in the size of the splenium of the corpus callosum in humans prompted the present examination of the corpus callosum in the rat. We have previously found that sex differences can vary with the rearing environment. Consequently, male and female rats were raised from weaning to 55 days of age in either a complex or an isolated environment. There were no sex differences in the size of the corpus callosum in sagittal cross section in these rats; however, rats of both sexes had a larger posterior third of the corpus callosum if they were raised in the complex environment. Because the corpus callosum continues to grow in size past 55 days of age, we examined socially housed rats at 113 days and again found no sex differences. The splenium was examined with electron microscopy in complex and isolation reared rats at 55 days of age. The ultrastructural analysis revealed differences that were not apparent from gross size measures. Females had more unmyelinated axons regardless of environment, and females from the complex environment had more myelinated axons than comparably housed males. In contrast, males in the complex environment had larger myelinated axons than females. Rats of both sexes from the complex environment had larger and more unmyelinated axons than isolated rats. In addition in myelinated axons, plasticity in the females occurred through changes in axon number and in males, through axon size. Thus sex differences exist in axonal number and size and the environment influences these differences.
Previous studies have shown that the number of dendritic spines and synapses in hippocampal CA1 s... more Previous studies have shown that the number of dendritic spines and synapses in hippocampal CA1 stratum radiatum decreases more than 30% between the proestrus (high estrogen) and estrus (low estrogen) phases of the rat estrous cycle [10,27]. In the present study, we investigated whether hippocampal synaptic plasticity, as measured by long-term potentiation (LTP), might also vary across the estrous cycle of the female rat. Male rats, and female rats at each phase of the estrous cycle were tested in either the morning or afternoon. There were no significant group differences in the pre-LTP I/0 curves. However, females examined during the afternoon of proestrus, the phase during which prior studies indicate synapse number to be highest, demonstrated the greatest degree of potentiation. Diestrus, proestrus and estrus females tested in the morning demonstrated similar amounts of potentiation. There were also significant differences in post-LTP I/0 curves between the afternoon proestrus females and males tested in the afternoon. These results suggest that gonadal hormones, interacting with the time of day, may regulate neural processes underlying learning and memory.
An earlier report from our laboratory demonstrated that there were sex differences in the dendrit... more An earlier report from our laboratory demonstrated that there were sex differences in the dendritic tree of granule neurons from the rat dentate gyrus (Juraska, Fitch, Henderson, & Rivers, 1985). To investigate the hormonal basis for these sex differences, we castrated or sham-operated male rats within hours of birth. At weaning, rats from both hormonal groups were assigned to either a complex or an isolated environment. After 1 month in the differential environments, the rats' brains were stained with Golgi-Cox, and the dendritic fields of granule neurons were quantified from 28 animals. Castrated males showed a response to the environments (complex > isolated) that was similar to that ofnormal females from previous work. This plasticity did not occur in the sham-operated males. However, the castrated males had fewer dendrites than did sham-operated males overall, so that there were no differences between the sham-operated and castrated males in the complex environment, where sex differences (female > male) had been previously found. Therefore, males that were neonatally castrated partially mirrored females in their pattern of dendritic sex differences in dentate granule neurons.
Adolescents and females experience worse outcomes of drug use compared to adults and males. This ... more Adolescents and females experience worse outcomes of drug use compared to adults and males. This could result from age-and sex-specific consequences of drug exposure on brain function and cognitive behavior. In the current study, we examined whether a history of intravenous methamphetamine (METH) self-administration impacted cognitive flexibility and 5-HT 2C R localization in the orbitofrontal cortex (OFC) in an age-and sex-dependent manner. Strategy shifting was assessed in male and female Sprague-Dawley rats that had self-administered METH (0.08 mg/kg/inf) or received non-contingent infusions of saline during periadolescence or young adulthood. After all rats reached adulthood, they were tested in an operant strategy shifting task and their brains were subsequently analyzed using immunofluorescence to quantify co-localization of 5-HT 2C receptors with parvalbumin interneurons in the OFC. We found that adolescent-onset females were the only group impaired during discrimination and reversal learning, but they did not exhibit changes in localization of 5-HT 2C receptors. In contrast, adult-onset males exhibited a significant increase in co-localization of 5-HT 2C receptors within parvalbumin interneurons in the left hemisphere of the OFC. These studies reveal that age and sex differences in drug-induced deficits in reversal learning and 5-HT 2C R co-localization with parvalbumin interneurons are dissociable and can manifest independently. In addition, these data highlight the potential for certain treatment approaches to be more suitable in some populations compared to others, such as alleviating drug-induced cognitive deficits as a focus for treatment in adolescent females.
The growth and organization of the developing brain are known to be influenced by hormones, but l... more The growth and organization of the developing brain are known to be influenced by hormones, but little is known about whether disruption of hormones affects cortical regions, such as mPFC. This region is particularly important given its involvement in executive functions and implication in the pathology of many neuropsychiatric disorders. Here, we examine the long-term effects of perinatal exposure to endocrine-disrupting compounds, the phthalates, on the mPFC and associated behavior. This investigation is pertinent as humans are ubiquitously exposed to phthalates through a variety of consumer products and phthalates can readily cross the placenta and be delivered to offspring via lactation. Pregnant dams orally consumed an environmentally relevant mixture of phthalates at 0, 200, or 1000 g/kg/d through pregnancy and for 10 d while lactating. As adults, offspring were tested in an attentional set-shifting task, which assesses cognitive flexibility. Brains were also examined in adulthood for stereological quantification of the number of neurons, glia, and synapses within the mPFC. We found that, independent of sex, perinatal phthalate exposure at either dose resulted in a reduction in neuron number, synapse number, and size of the mPFC and a deficit in cognitive flexibility. Interestingly, the number of synapses was correlated with cognitive flexibility, such that rats with fewer synapses were less cognitively flexible than those with more synapses. These results demonstrate that perinatal phthalate exposure can have long-term effects on the cortex and behavior of both male and female rats.
The expression of several inflammatory cytokines that inhibit synaptic plasticity and hippocampal... more The expression of several inflammatory cytokines that inhibit synaptic plasticity and hippocampal-dependent learning and memory is higher in the brains of aged mice compared to young adults after peripheral injection of lipopolysaccharide (LPS). In this study we investigated whether the exaggerated inflammatory cytokine response in the hippocampus of aged mice after IP injection of LPS is associated with architectural changes to dendrites of pyramidal neurons in the dorsal CA1 hippocampus. Compared to young adults, aged mice had higher basal expression of MHC class II, lower basal expression of two neurotrophins, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), and a decrease in total dendritic length in both the basal and apical tree. After IP LPS administration, expression of IL-1beta, IL-6, and TNFalpha mRNA was higher in hippocampus of aged mice compared to young adults whereas NGF and BDNF mRNA was reduced similarly in both age groups. The basal dendritic tree was not affected by LPS in either adult or aged mice 72h after treatment; however, length and branching of the apical tree was reduced by LPS in aged but not adult mice. The present findings indicate that a peripheral infection in the aged can cause a heightened inflammatory cytokine response in the hippocampus and atrophy of hippocampal neurons. Architectural changes to dorsal CA1 hippocampal neurons may contribute to cognitive disorders evident in elderly patients with an infection.
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Papers by Janice Juraska