Adverse early-life experiences, including various forms of early-life stress, have consistently b... more Adverse early-life experiences, including various forms of early-life stress, have consistently been linked with vulnerability to cognitive and emotional disorders later in life. Understanding the mechanisms underlying the enduring consequences of early-life stress is an active area of research, because this knowledge is critical for developing potential interventions. Animal models of early-life stress typically rely on manipulating maternal/parental presence and care, because these are the major sources of early-life experiences in humans. Diverse models have been created, and have resulted in a wealth of behavioral outcomes. Here we focus on recent findings highlighting early-life stress-induced behavioral disturbances, ranging from hippocampus-dependent memory deficits to problems with experiencing pleasure (anhedonia). The use of naturalistic animal models of chronic early-life stress provides insight into the spectrum of cognitive and emotional outcomes and enables probing the underlying mechanisms using molecular-, cellular-, and network-level approaches.
Stress influences memory, an adaptive process crucial for survival. During stress, hippocampal sy... more Stress influences memory, an adaptive process crucial for survival. During stress, hippocampal synapses are bathed in a mixture of stress-released molecules, yet it is unknown whether or how these interact to mediate the effects of stress on memory. Here, we demonstrate novel synergistic actions of corticosterone and corticotropin-releasing hormone (CRH) on synaptic physiology and dendritic spine structure that mediate the profound effects of acute concurrent stresses on memory. Spatial memory in mice was impaired enduringly after acute concurrent stresses resulting from loss of synaptic potentiation associated with disrupted structure of synapse-bearing dendritic spines. Combined application of the stress hormones corticosterone and CRH recapitulated the physiological and structural defects provoked by acute stresses. Mechanistically, corticosterone and CRH, via their cognate receptors, acted synergistically on the spine-actin regulator RhoA, promoting its deactivation and degradation, respectively, and destabilizing spines. Accordingly, blocking the receptors of both hormones, but not each alone, rescued memory. Therefore, the synergistic actions of corticosterone and CRH at hippocampal synapses underlie memory impairments after concurrent and perhaps also single, severe acute stresses, with potential implications to spatial memory dysfunction in, for example, posttraumatic stress disorder.
Resilience to stress-related emotional disorders is governed in part by early-life experiences. H... more Resilience to stress-related emotional disorders is governed in part by early-life experiences. Here we demonstrate experience-dependent reprogramming of stress-sensitive hypothalamic neurons, which takes place through modification of neuronal gene expression via epigenetic mechanisms. Specifically, we found that augmented maternal care reduced glutamatergic synapses onto stress-sensitive hypothalamic neurons and repressed expression of the stress-responsive gene, Crh. In hypothalamus in vitro, reduced glutamatergic neurotransmission recapitulated the repressive effects of augmented maternal care on Crh, and this required recruitment of the transcriptional repressor repressor element-1 silencing transcription factor/neuron restrictive silencing factor (NRSF). Increased NRSF binding to chromatin was accompanied by sequential repressive epigenetic changes which outlasted NRSF binding. chromatin immunoprecipitation-seq analyses of NRSF targets identified gene networks that, in addition to Crh, likely contributed to the augmented care-induced phenotype, including diminished depression-like and anxiety-like behaviors. Together, we believe these findings provide the first causal link between enriched neonatal experience, synaptic refinement and induction of epigenetic processes within specific neurons. They uncover a novel mechanistic pathway from neonatal environment to emotional resilience.
Environmental chemical exposures during critical windows of development may contribute to the esc... more Environmental chemical exposures during critical windows of development may contribute to the escalating prevalence of obesity. We tested the hypothesis that prenatal exposure to diesel exhaust particles (DEP), a primary component of air pollution, would prime microglia long-term, resulting in exacerbated metabolic and affective outcomes following exposure to a high-fat diet in adulthood. Time-mated mouse dams were intermittently exposed to respiratory instillations of either vehicle (VEH) or DEP throughout gestation. Adult male and female offspring were then fed either a low-fat diet (LFD) or high-fat diet (HFD) for 9 weeks. The male offspring of DEP-exposed dams exhibited exaggerated weight gain, insulin resistance, and anxiety-like behavior on HFD compared to the male offspring of VEHexposed dams, whereas female offspring did not differ according to prenatal treatment. Furthermore, HFD induced evidence of macrophage infiltration of both adipose tissue and the brain in both sexes, but these cells were more activated specifically in DEP/HFD males. DEP/HFD males also expressed markedly higher levels of microglial/macrophage, but not astrocyte, activation markers in the hippocampus, whereas females exhibited only a suppression of astrocyte activation markers due to HFD. In a second experiment, DEP male offspring mounted an exaggerated peripheral IL-1b response to an LPS challenge at postnatal day (P)30, whereas their central IL-1b response did not differ from VEH male offspring, which is suggestive of macrophage priming due to prenatal DEP exposure. In sum, prenatal air pollution exposure ''programs'' offspring for increased susceptibility to diet-induced metabolic, behavioral, and neuroinflammatory changes in adulthood in a sexually dimorphic manner. j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / y b r b i Please cite this article in press as: Bolton, J.L., et al. Prenatal air pollution exposure induces sexually dimorphic fetal programming of metabolic and neuroinflammatory outcomes in adult offspring. Brain Behav. Immun. (2013), http://dx.2 J.L. Bolton et al. / Brain, Behavior, and Immunity xxx (2013) xxx-xxx Please cite this article in press as: Bolton, J.L., et al. Prenatal air pollution exposure induces sexually dimorphic fetal programming of metabolic and neuroinflammatory outcomes in adult offspring. Brain Behav. Immun. (2013), http://dx.
The present study investigated the preference of prepubescent and adult rats for an unrelated con... more The present study investigated the preference of prepubescent and adult rats for an unrelated conspecific over a closely related conspecific (e.g., father, mother). Preference was measured by the amount of time spent in the vicinity of the stimulus animals as well as who was visited first. To prevent mating behavior, stimulus animals were housed behind wire-mesh. Experiment 1 determined if adult female offspring prefer an unrelated, unfamiliar adult male or their father. The preference of adult female rats was independent of kinship. Experiment 2 evaluated the preference of prepubescent female and male offspring for an unrelated, unfamiliar adult male or their father. The preference of prepubescent female and male rats was also independent of kinship. Experiment 3 evaluated the preference of adult male offspring for an unrelated, unfamiliar adult female or their mother. The preference of adult male rats was independent of kinship. In summary, prepubescent and adult rats do not demonstrate preference for kin vs. non-kin (as measured by time spent near stimulus animals or who was visited first). Although kin recognition provides a mechanism for inbreeding avoidance , in the present study adult rats show no evidence of inbreeding avoidance.
Obesity is now epidemic worldwide. Beyond associated diseases such as diabetes, obesity is linked... more Obesity is now epidemic worldwide. Beyond associated diseases such as diabetes, obesity is linked to neuropsychiatric disorders such as depression. Alarmingly, maternal obesity and high-fat diet consumption during gestation/lactation may “program” offspring long-term for increased obesity themselves, along with increased vulnerability to mood disorders. We review the evidence that programming of brain and behavior by perinatal diet is propagated by inflammatory mechanisms, as obesity and high-fat diets are independently associated with exaggerated systemic levels of inflammatory mediators. Due to the recognized dual role of these immune molecules (e.g., interleukin [IL]-6, IL-1β) in placental function and brain development, any disruption of their delicate balance with growth factors or neurotransmitters (e.g., serotonin) by inflammation early in life can permanently alter the trajectory of fetal brain development. Finally, epigenetic regulation of inflammatory pathways is a likely candidate for persistent changes in metabolic and brain function as a consequence of the perinatal environment.
Research indicates gender differences in sensitivity to psychomotor stimulants. Preclinical work ... more Research indicates gender differences in sensitivity to psychomotor stimulants. Preclinical work investigating the interaction between drugs of abuse and sex-specific behaviors, such as sexual behavior, is critical to the explanation of such gender differences in humans. A number of behavioral paradigms can be used to model aspects of human sexual behavior in animal subjects. Although traditional assessment of the reflexive, lordosis posture of the female rat has been used to map the neuroanatomical and neurochemical systems that contribute to uniquely female copulatory behavior, the additional behavioral paradigms discussed in the current review have helped us expand our description of the appetitive and consummatory patterns of sexual behavior in the female rat. Measuring appetitive behaviors is particularly important for assessing sexual motivation, the equivalent of “desire” in humans. By investigating the effects of commonly abused drugs on female sexual motivation, we are beginning to elucidate the role of dopaminergic neurotransmission in female sexual motivation, a neural system also known to be critical to the neurobiology of drug addiction. A better understanding of the nexus of sex and drugs in the female brain will help advance our understanding of motivation in general and explain how psychomotor stimulants affect males and females differently.
Environmental chemical exposures during critical windows of development may contribute to the
es... more Environmental chemical exposures during critical windows of development may contribute to the
escalating prevalence of obesity. We tested the hypothesis that prenatal exposure to diesel exhaust
particles (DEP), a primary component of air pollution, would prime microglia long-term, resulting in
exacerbated metabolic and affective outcomes following exposure to a high-fat diet in adulthood.
Time-mated mouse dams were intermittently exposed to respiratory instillations of either vehicle
(VEH) or DEP throughout gestation. Adult male and female offspring were then fed either a low-fat diet
(LFD) or high-fat diet (HFD) for 9 weeks. The male offspring of DEP-exposed dams exhibited exaggerated
weight gain, insulin resistance, and anxiety-like behavior on HFD compared to the male offspring of VEHexposed
dams, whereas female offspring did not differ according to prenatal treatment. Furthermore,
HFD induced evidence of macrophage infiltration of both adipose tissue and the brain in both sexes,
but these cells were more activated specifically in DEP/HFD males. DEP/HFD males also expressed markedly
higher levels of microglial/macrophage, but not astrocyte, activation markers in the hippocampus,
whereas females exhibited only a suppression of astrocyte activation markers due to HFD. In a second
experiment, DEP male offspring mounted an exaggerated peripheral IL-1b response to an LPS challenge
at postnatal day (P)30, whereas their central IL-1b response did not differ from VEH male offspring, which
is suggestive of macrophage priming due to prenatal DEP exposure. In sum, prenatal air pollution
exposure ‘‘programs’’ offspring for increased susceptibility to diet-induced metabolic, behavioral, and
neuroinflammatory changes in adulthood in a sexually dimorphic manner.
Background: Low socioeconomic status is consistently associated with reduced physical and
mental... more Background: Low socioeconomic status is consistently associated with reduced physical and
mental
health, but the mechanisms remain unclear. Increased levels of urban air pollutants interacting
with parental stress have been proposed to explain health disparities in respiratory disease,
but the impact of such interactions on mental health is unknown.
Objectives: We aimed to determine whether prenatal air pollution exposure and stress during
pregnancy act synergistically on offspring to induce a neuroinflammatory response and subsequent
neurocognitive
disorders in adulthood.
Methods: Mouse dams were intermittently exposed via oropharyngeal aspiration to diesel exhaust
particles (DEP; 50 μg × 6 doses) or vehicle throughout gestation. This exposure was combined with
standard housing or nest material restriction (NR; a novel model of maternal stress) during the last
third of gestation.
Results: Adult (postnatal day 60) offspring of dams that experienced both stressors (DEP and
NR) displayed increased anxiety, but only male offspring of this group had impaired cognition.
Furthermore, maternal DEP exposure increased proinflammatory
interleukin (IL)-1β levels
within the brains of adult males but not females, and maternal DEP and NR both decreased
anti-inflammatory IL‑10 in male, but not female, brains. Similarly, only DEP/NR males showed
increased expression of the innate immune recognition gene toll-like receptor 4 (Tlr4) and its
downstream effector, caspase-1.
Conclusions: These results show that maternal stress during late gestation increases the susceptibility
of offspring—particularly males—to the deleterious effects of prenatal
air pollutant exposure,
which may be due to a synergism of these factors acting on innate immune recognition genes and
downstream neuroinflammatory cascades within the developing brain.
Abstract Emerging evidence suggests environmental chemical exposures during critical windows of d... more Abstract Emerging evidence suggests environmental chemical exposures during critical windows of development may contribute to the escalating prevalence of obesity. We tested the hypothesis that prenatal air pollution exposure would predispose the offspring to weight gain in adulthood. Pregnant mice were exposed to filtered air (FA) or diesel exhaust (DE) on embryonic days (E) 9-17. Prenatal DE induced a significant fetal brain cytokine response at E18 (46–390% over FA).
The present study investigated the preference of prepubescent and adult rats for an unrelated con... more The present study investigated the preference of prepubescent and adult rats for an unrelated conspecific
over a closely related conspecific (e.g., father, mother). Preference was measured by the amount of time
spent in the vicinity of the stimulus animals as well as who was visited first. To prevent mating behavior,
stimulus animals were housed behind wire-mesh. Experiment 1 determined if adult female offspring
prefer an unrelated, unfamiliar adult male or their father. The preference of adult female rats was independent
of kinship. Experiment 2 evaluated the preference of prepubescent female and male offspring
for an unrelated, unfamiliar adult male or their father. The preference of prepubescent female and male
rats was also independent of kinship. Experiment 3 evaluated the preference of adult male offspring for
an unrelated, unfamiliar adult female or their mother. The preference of adult male rats was independent
of kinship. In summary, prepubescent and adult rats do not demonstrate preference for kin vs. non-kin
(as measured by time spent near stimulus animals or who was visited first). Although kin recognition
provides a mechanism for inbreeding avoidance (Wilson, 1987), in the present study adult rats show no
evidence of inbreeding avoidance.
The present study was designed to determine if male physiology and male reproductive behavior pre... more The present study was designed to determine if male physiology and male reproductive behavior predict reproductive
success in Long–Evans rats. Mating behavior was observed in sexually naïve, naturally cycling female
rats during behavioral estrous that were given the opportunity to mate with two males simultaneously.
DNA analysis of offspring born following these mating encounters was used to identify the paternity of each
pup. In order to assess the effect of mate choice during these mating encounters on reproductive success, one
male rat in each pair was categorized as the preferred mate if the female spent more time (>50%) with him
during the mating test of the present study. Furthermore, each male in the pairs was categorized as “attractive”
or “non-attractive” by computing the number of females that preferred each male across many mating
tests. Similar to results reported in Lovell et al. (2007), during 76% of these mating tests the same male rat in
each pair was preferred by different female rats. Overall attractiveness of individual male rats predicted reproductive
success in the present study. Interestingly, “attractive” males sired significantly FEWER pups
than “non-attractive” males. Neither behavioral (e.g., latency to first sexual stimulation, number of sexual
stimulations) nor physiological measures (e.g., body weight, urinary testosterone levels) of male rats predicted
their reproductive success. In conclusion, the present results indicate that certain features of some
males are more attractive to females, but attractive males are at a reproductive disadvantage (as measured
by the number of pups sired). Although basal urinary testosterone levels did not differ between males that
sired the majority of pups in a litter and males that sired few or none of the pups in a litter, aggression
and/or other physiological measures of fertility (e.g., penile reflexes) may differ between males that are attractive
to females and those that have a reproductive advantage.
The present study evaluated the effects of methamphetamine (MA) on sexual behavior in female rats... more The present study evaluated the effects of methamphetamine (MA) on sexual behavior in female rats. In
Experiment 1, ovariectomized, hormone-primed rats were injected with MA (1.0 mg/kg, i.p.) or saline prior to
a test for mate choice wherein females could mate with two males simultaneously. Female rats treated with
saline returned to their preferred mate faster after receiving intromissions and visited their preferred mate at
a higher rate than their non-preferred mate. In contrast, MA-treated female rats spent a similar amount of
time with their preferred and non-preferred mate and failed to return to their preferred mate faster than to
their non-preferred mate following intromissions. Two weeks later, the females received the same drug
treatment but were tested for partner preference wherein females could spend time near a male or female
stimulus rat. All subjects spent more time near the male stimulus than the female stimulus. However, the MAtreated
rats visited the male stimulus more frequently and spent less time near the female stimulus than the
saline-treated rats. Similar to Experiment 1, female rats in Experiment 2 were tested for mate choice and then
two weeks later tested for partner preference; however, females received three daily injections of MA
(1.0 mg/kg, i.p.) or saline. Females treated chronically with MA returned to both males faster following
intromissions than females treated with saline, independent of preference (i.e., preferred mate and nonpreferred
mate). Furthermore, MA-treated rats were more likely to leave either male (i.e., preferred or nonpreferred
mate) than saline-treated rats after receiving sexual stimulation. Although MA-treated subjects
spent more time near the male stimulus than the female stimulus, they spent less time near either when
compared to saline-treated subjects. The present results demonstrate that MA affects sexual behavior in
female rats partly by increasing locomotion and partly by directly affecting sexual behavior.
Adverse early-life experiences, including various forms of early-life stress, have consistently b... more Adverse early-life experiences, including various forms of early-life stress, have consistently been linked with vulnerability to cognitive and emotional disorders later in life. Understanding the mechanisms underlying the enduring consequences of early-life stress is an active area of research, because this knowledge is critical for developing potential interventions. Animal models of early-life stress typically rely on manipulating maternal/parental presence and care, because these are the major sources of early-life experiences in humans. Diverse models have been created, and have resulted in a wealth of behavioral outcomes. Here we focus on recent findings highlighting early-life stress-induced behavioral disturbances, ranging from hippocampus-dependent memory deficits to problems with experiencing pleasure (anhedonia). The use of naturalistic animal models of chronic early-life stress provides insight into the spectrum of cognitive and emotional outcomes and enables probing the underlying mechanisms using molecular-, cellular-, and network-level approaches.
Stress influences memory, an adaptive process crucial for survival. During stress, hippocampal sy... more Stress influences memory, an adaptive process crucial for survival. During stress, hippocampal synapses are bathed in a mixture of stress-released molecules, yet it is unknown whether or how these interact to mediate the effects of stress on memory. Here, we demonstrate novel synergistic actions of corticosterone and corticotropin-releasing hormone (CRH) on synaptic physiology and dendritic spine structure that mediate the profound effects of acute concurrent stresses on memory. Spatial memory in mice was impaired enduringly after acute concurrent stresses resulting from loss of synaptic potentiation associated with disrupted structure of synapse-bearing dendritic spines. Combined application of the stress hormones corticosterone and CRH recapitulated the physiological and structural defects provoked by acute stresses. Mechanistically, corticosterone and CRH, via their cognate receptors, acted synergistically on the spine-actin regulator RhoA, promoting its deactivation and degradation, respectively, and destabilizing spines. Accordingly, blocking the receptors of both hormones, but not each alone, rescued memory. Therefore, the synergistic actions of corticosterone and CRH at hippocampal synapses underlie memory impairments after concurrent and perhaps also single, severe acute stresses, with potential implications to spatial memory dysfunction in, for example, posttraumatic stress disorder.
Resilience to stress-related emotional disorders is governed in part by early-life experiences. H... more Resilience to stress-related emotional disorders is governed in part by early-life experiences. Here we demonstrate experience-dependent reprogramming of stress-sensitive hypothalamic neurons, which takes place through modification of neuronal gene expression via epigenetic mechanisms. Specifically, we found that augmented maternal care reduced glutamatergic synapses onto stress-sensitive hypothalamic neurons and repressed expression of the stress-responsive gene, Crh. In hypothalamus in vitro, reduced glutamatergic neurotransmission recapitulated the repressive effects of augmented maternal care on Crh, and this required recruitment of the transcriptional repressor repressor element-1 silencing transcription factor/neuron restrictive silencing factor (NRSF). Increased NRSF binding to chromatin was accompanied by sequential repressive epigenetic changes which outlasted NRSF binding. chromatin immunoprecipitation-seq analyses of NRSF targets identified gene networks that, in addition to Crh, likely contributed to the augmented care-induced phenotype, including diminished depression-like and anxiety-like behaviors. Together, we believe these findings provide the first causal link between enriched neonatal experience, synaptic refinement and induction of epigenetic processes within specific neurons. They uncover a novel mechanistic pathway from neonatal environment to emotional resilience.
Environmental chemical exposures during critical windows of development may contribute to the esc... more Environmental chemical exposures during critical windows of development may contribute to the escalating prevalence of obesity. We tested the hypothesis that prenatal exposure to diesel exhaust particles (DEP), a primary component of air pollution, would prime microglia long-term, resulting in exacerbated metabolic and affective outcomes following exposure to a high-fat diet in adulthood. Time-mated mouse dams were intermittently exposed to respiratory instillations of either vehicle (VEH) or DEP throughout gestation. Adult male and female offspring were then fed either a low-fat diet (LFD) or high-fat diet (HFD) for 9 weeks. The male offspring of DEP-exposed dams exhibited exaggerated weight gain, insulin resistance, and anxiety-like behavior on HFD compared to the male offspring of VEHexposed dams, whereas female offspring did not differ according to prenatal treatment. Furthermore, HFD induced evidence of macrophage infiltration of both adipose tissue and the brain in both sexes, but these cells were more activated specifically in DEP/HFD males. DEP/HFD males also expressed markedly higher levels of microglial/macrophage, but not astrocyte, activation markers in the hippocampus, whereas females exhibited only a suppression of astrocyte activation markers due to HFD. In a second experiment, DEP male offspring mounted an exaggerated peripheral IL-1b response to an LPS challenge at postnatal day (P)30, whereas their central IL-1b response did not differ from VEH male offspring, which is suggestive of macrophage priming due to prenatal DEP exposure. In sum, prenatal air pollution exposure ''programs'' offspring for increased susceptibility to diet-induced metabolic, behavioral, and neuroinflammatory changes in adulthood in a sexually dimorphic manner. j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / y b r b i Please cite this article in press as: Bolton, J.L., et al. Prenatal air pollution exposure induces sexually dimorphic fetal programming of metabolic and neuroinflammatory outcomes in adult offspring. Brain Behav. Immun. (2013), http://dx.2 J.L. Bolton et al. / Brain, Behavior, and Immunity xxx (2013) xxx-xxx Please cite this article in press as: Bolton, J.L., et al. Prenatal air pollution exposure induces sexually dimorphic fetal programming of metabolic and neuroinflammatory outcomes in adult offspring. Brain Behav. Immun. (2013), http://dx.
The present study investigated the preference of prepubescent and adult rats for an unrelated con... more The present study investigated the preference of prepubescent and adult rats for an unrelated conspecific over a closely related conspecific (e.g., father, mother). Preference was measured by the amount of time spent in the vicinity of the stimulus animals as well as who was visited first. To prevent mating behavior, stimulus animals were housed behind wire-mesh. Experiment 1 determined if adult female offspring prefer an unrelated, unfamiliar adult male or their father. The preference of adult female rats was independent of kinship. Experiment 2 evaluated the preference of prepubescent female and male offspring for an unrelated, unfamiliar adult male or their father. The preference of prepubescent female and male rats was also independent of kinship. Experiment 3 evaluated the preference of adult male offspring for an unrelated, unfamiliar adult female or their mother. The preference of adult male rats was independent of kinship. In summary, prepubescent and adult rats do not demonstrate preference for kin vs. non-kin (as measured by time spent near stimulus animals or who was visited first). Although kin recognition provides a mechanism for inbreeding avoidance , in the present study adult rats show no evidence of inbreeding avoidance.
Obesity is now epidemic worldwide. Beyond associated diseases such as diabetes, obesity is linked... more Obesity is now epidemic worldwide. Beyond associated diseases such as diabetes, obesity is linked to neuropsychiatric disorders such as depression. Alarmingly, maternal obesity and high-fat diet consumption during gestation/lactation may “program” offspring long-term for increased obesity themselves, along with increased vulnerability to mood disorders. We review the evidence that programming of brain and behavior by perinatal diet is propagated by inflammatory mechanisms, as obesity and high-fat diets are independently associated with exaggerated systemic levels of inflammatory mediators. Due to the recognized dual role of these immune molecules (e.g., interleukin [IL]-6, IL-1β) in placental function and brain development, any disruption of their delicate balance with growth factors or neurotransmitters (e.g., serotonin) by inflammation early in life can permanently alter the trajectory of fetal brain development. Finally, epigenetic regulation of inflammatory pathways is a likely candidate for persistent changes in metabolic and brain function as a consequence of the perinatal environment.
Research indicates gender differences in sensitivity to psychomotor stimulants. Preclinical work ... more Research indicates gender differences in sensitivity to psychomotor stimulants. Preclinical work investigating the interaction between drugs of abuse and sex-specific behaviors, such as sexual behavior, is critical to the explanation of such gender differences in humans. A number of behavioral paradigms can be used to model aspects of human sexual behavior in animal subjects. Although traditional assessment of the reflexive, lordosis posture of the female rat has been used to map the neuroanatomical and neurochemical systems that contribute to uniquely female copulatory behavior, the additional behavioral paradigms discussed in the current review have helped us expand our description of the appetitive and consummatory patterns of sexual behavior in the female rat. Measuring appetitive behaviors is particularly important for assessing sexual motivation, the equivalent of “desire” in humans. By investigating the effects of commonly abused drugs on female sexual motivation, we are beginning to elucidate the role of dopaminergic neurotransmission in female sexual motivation, a neural system also known to be critical to the neurobiology of drug addiction. A better understanding of the nexus of sex and drugs in the female brain will help advance our understanding of motivation in general and explain how psychomotor stimulants affect males and females differently.
Environmental chemical exposures during critical windows of development may contribute to the
es... more Environmental chemical exposures during critical windows of development may contribute to the
escalating prevalence of obesity. We tested the hypothesis that prenatal exposure to diesel exhaust
particles (DEP), a primary component of air pollution, would prime microglia long-term, resulting in
exacerbated metabolic and affective outcomes following exposure to a high-fat diet in adulthood.
Time-mated mouse dams were intermittently exposed to respiratory instillations of either vehicle
(VEH) or DEP throughout gestation. Adult male and female offspring were then fed either a low-fat diet
(LFD) or high-fat diet (HFD) for 9 weeks. The male offspring of DEP-exposed dams exhibited exaggerated
weight gain, insulin resistance, and anxiety-like behavior on HFD compared to the male offspring of VEHexposed
dams, whereas female offspring did not differ according to prenatal treatment. Furthermore,
HFD induced evidence of macrophage infiltration of both adipose tissue and the brain in both sexes,
but these cells were more activated specifically in DEP/HFD males. DEP/HFD males also expressed markedly
higher levels of microglial/macrophage, but not astrocyte, activation markers in the hippocampus,
whereas females exhibited only a suppression of astrocyte activation markers due to HFD. In a second
experiment, DEP male offspring mounted an exaggerated peripheral IL-1b response to an LPS challenge
at postnatal day (P)30, whereas their central IL-1b response did not differ from VEH male offspring, which
is suggestive of macrophage priming due to prenatal DEP exposure. In sum, prenatal air pollution
exposure ‘‘programs’’ offspring for increased susceptibility to diet-induced metabolic, behavioral, and
neuroinflammatory changes in adulthood in a sexually dimorphic manner.
Background: Low socioeconomic status is consistently associated with reduced physical and
mental... more Background: Low socioeconomic status is consistently associated with reduced physical and
mental
health, but the mechanisms remain unclear. Increased levels of urban air pollutants interacting
with parental stress have been proposed to explain health disparities in respiratory disease,
but the impact of such interactions on mental health is unknown.
Objectives: We aimed to determine whether prenatal air pollution exposure and stress during
pregnancy act synergistically on offspring to induce a neuroinflammatory response and subsequent
neurocognitive
disorders in adulthood.
Methods: Mouse dams were intermittently exposed via oropharyngeal aspiration to diesel exhaust
particles (DEP; 50 μg × 6 doses) or vehicle throughout gestation. This exposure was combined with
standard housing or nest material restriction (NR; a novel model of maternal stress) during the last
third of gestation.
Results: Adult (postnatal day 60) offspring of dams that experienced both stressors (DEP and
NR) displayed increased anxiety, but only male offspring of this group had impaired cognition.
Furthermore, maternal DEP exposure increased proinflammatory
interleukin (IL)-1β levels
within the brains of adult males but not females, and maternal DEP and NR both decreased
anti-inflammatory IL‑10 in male, but not female, brains. Similarly, only DEP/NR males showed
increased expression of the innate immune recognition gene toll-like receptor 4 (Tlr4) and its
downstream effector, caspase-1.
Conclusions: These results show that maternal stress during late gestation increases the susceptibility
of offspring—particularly males—to the deleterious effects of prenatal
air pollutant exposure,
which may be due to a synergism of these factors acting on innate immune recognition genes and
downstream neuroinflammatory cascades within the developing brain.
Abstract Emerging evidence suggests environmental chemical exposures during critical windows of d... more Abstract Emerging evidence suggests environmental chemical exposures during critical windows of development may contribute to the escalating prevalence of obesity. We tested the hypothesis that prenatal air pollution exposure would predispose the offspring to weight gain in adulthood. Pregnant mice were exposed to filtered air (FA) or diesel exhaust (DE) on embryonic days (E) 9-17. Prenatal DE induced a significant fetal brain cytokine response at E18 (46–390% over FA).
The present study investigated the preference of prepubescent and adult rats for an unrelated con... more The present study investigated the preference of prepubescent and adult rats for an unrelated conspecific
over a closely related conspecific (e.g., father, mother). Preference was measured by the amount of time
spent in the vicinity of the stimulus animals as well as who was visited first. To prevent mating behavior,
stimulus animals were housed behind wire-mesh. Experiment 1 determined if adult female offspring
prefer an unrelated, unfamiliar adult male or their father. The preference of adult female rats was independent
of kinship. Experiment 2 evaluated the preference of prepubescent female and male offspring
for an unrelated, unfamiliar adult male or their father. The preference of prepubescent female and male
rats was also independent of kinship. Experiment 3 evaluated the preference of adult male offspring for
an unrelated, unfamiliar adult female or their mother. The preference of adult male rats was independent
of kinship. In summary, prepubescent and adult rats do not demonstrate preference for kin vs. non-kin
(as measured by time spent near stimulus animals or who was visited first). Although kin recognition
provides a mechanism for inbreeding avoidance (Wilson, 1987), in the present study adult rats show no
evidence of inbreeding avoidance.
The present study was designed to determine if male physiology and male reproductive behavior pre... more The present study was designed to determine if male physiology and male reproductive behavior predict reproductive
success in Long–Evans rats. Mating behavior was observed in sexually naïve, naturally cycling female
rats during behavioral estrous that were given the opportunity to mate with two males simultaneously.
DNA analysis of offspring born following these mating encounters was used to identify the paternity of each
pup. In order to assess the effect of mate choice during these mating encounters on reproductive success, one
male rat in each pair was categorized as the preferred mate if the female spent more time (>50%) with him
during the mating test of the present study. Furthermore, each male in the pairs was categorized as “attractive”
or “non-attractive” by computing the number of females that preferred each male across many mating
tests. Similar to results reported in Lovell et al. (2007), during 76% of these mating tests the same male rat in
each pair was preferred by different female rats. Overall attractiveness of individual male rats predicted reproductive
success in the present study. Interestingly, “attractive” males sired significantly FEWER pups
than “non-attractive” males. Neither behavioral (e.g., latency to first sexual stimulation, number of sexual
stimulations) nor physiological measures (e.g., body weight, urinary testosterone levels) of male rats predicted
their reproductive success. In conclusion, the present results indicate that certain features of some
males are more attractive to females, but attractive males are at a reproductive disadvantage (as measured
by the number of pups sired). Although basal urinary testosterone levels did not differ between males that
sired the majority of pups in a litter and males that sired few or none of the pups in a litter, aggression
and/or other physiological measures of fertility (e.g., penile reflexes) may differ between males that are attractive
to females and those that have a reproductive advantage.
The present study evaluated the effects of methamphetamine (MA) on sexual behavior in female rats... more The present study evaluated the effects of methamphetamine (MA) on sexual behavior in female rats. In
Experiment 1, ovariectomized, hormone-primed rats were injected with MA (1.0 mg/kg, i.p.) or saline prior to
a test for mate choice wherein females could mate with two males simultaneously. Female rats treated with
saline returned to their preferred mate faster after receiving intromissions and visited their preferred mate at
a higher rate than their non-preferred mate. In contrast, MA-treated female rats spent a similar amount of
time with their preferred and non-preferred mate and failed to return to their preferred mate faster than to
their non-preferred mate following intromissions. Two weeks later, the females received the same drug
treatment but were tested for partner preference wherein females could spend time near a male or female
stimulus rat. All subjects spent more time near the male stimulus than the female stimulus. However, the MAtreated
rats visited the male stimulus more frequently and spent less time near the female stimulus than the
saline-treated rats. Similar to Experiment 1, female rats in Experiment 2 were tested for mate choice and then
two weeks later tested for partner preference; however, females received three daily injections of MA
(1.0 mg/kg, i.p.) or saline. Females treated chronically with MA returned to both males faster following
intromissions than females treated with saline, independent of preference (i.e., preferred mate and nonpreferred
mate). Furthermore, MA-treated rats were more likely to leave either male (i.e., preferred or nonpreferred
mate) than saline-treated rats after receiving sexual stimulation. Although MA-treated subjects
spent more time near the male stimulus than the female stimulus, they spent less time near either when
compared to saline-treated subjects. The present results demonstrate that MA affects sexual behavior in
female rats partly by increasing locomotion and partly by directly affecting sexual behavior.
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Papers by Jessica Bolton
escalating prevalence of obesity. We tested the hypothesis that prenatal exposure to diesel exhaust
particles (DEP), a primary component of air pollution, would prime microglia long-term, resulting in
exacerbated metabolic and affective outcomes following exposure to a high-fat diet in adulthood.
Time-mated mouse dams were intermittently exposed to respiratory instillations of either vehicle
(VEH) or DEP throughout gestation. Adult male and female offspring were then fed either a low-fat diet
(LFD) or high-fat diet (HFD) for 9 weeks. The male offspring of DEP-exposed dams exhibited exaggerated
weight gain, insulin resistance, and anxiety-like behavior on HFD compared to the male offspring of VEHexposed
dams, whereas female offspring did not differ according to prenatal treatment. Furthermore,
HFD induced evidence of macrophage infiltration of both adipose tissue and the brain in both sexes,
but these cells were more activated specifically in DEP/HFD males. DEP/HFD males also expressed markedly
higher levels of microglial/macrophage, but not astrocyte, activation markers in the hippocampus,
whereas females exhibited only a suppression of astrocyte activation markers due to HFD. In a second
experiment, DEP male offspring mounted an exaggerated peripheral IL-1b response to an LPS challenge
at postnatal day (P)30, whereas their central IL-1b response did not differ from VEH male offspring, which
is suggestive of macrophage priming due to prenatal DEP exposure. In sum, prenatal air pollution
exposure ‘‘programs’’ offspring for increased susceptibility to diet-induced metabolic, behavioral, and
neuroinflammatory changes in adulthood in a sexually dimorphic manner.
mental
health, but the mechanisms remain unclear. Increased levels of urban air pollutants interacting
with parental stress have been proposed to explain health disparities in respiratory disease,
but the impact of such interactions on mental health is unknown.
Objectives: We aimed to determine whether prenatal air pollution exposure and stress during
pregnancy act synergistically on offspring to induce a neuroinflammatory response and subsequent
neurocognitive
disorders in adulthood.
Methods: Mouse dams were intermittently exposed via oropharyngeal aspiration to diesel exhaust
particles (DEP; 50 μg × 6 doses) or vehicle throughout gestation. This exposure was combined with
standard housing or nest material restriction (NR; a novel model of maternal stress) during the last
third of gestation.
Results: Adult (postnatal day 60) offspring of dams that experienced both stressors (DEP and
NR) displayed increased anxiety, but only male offspring of this group had impaired cognition.
Furthermore, maternal DEP exposure increased proinflammatory
interleukin (IL)-1β levels
within the brains of adult males but not females, and maternal DEP and NR both decreased
anti-inflammatory IL‑10 in male, but not female, brains. Similarly, only DEP/NR males showed
increased expression of the innate immune recognition gene toll-like receptor 4 (Tlr4) and its
downstream effector, caspase-1.
Conclusions: These results show that maternal stress during late gestation increases the susceptibility
of offspring—particularly males—to the deleterious effects of prenatal
air pollutant exposure,
which may be due to a synergism of these factors acting on innate immune recognition genes and
downstream neuroinflammatory cascades within the developing brain.
over a closely related conspecific (e.g., father, mother). Preference was measured by the amount of time
spent in the vicinity of the stimulus animals as well as who was visited first. To prevent mating behavior,
stimulus animals were housed behind wire-mesh. Experiment 1 determined if adult female offspring
prefer an unrelated, unfamiliar adult male or their father. The preference of adult female rats was independent
of kinship. Experiment 2 evaluated the preference of prepubescent female and male offspring
for an unrelated, unfamiliar adult male or their father. The preference of prepubescent female and male
rats was also independent of kinship. Experiment 3 evaluated the preference of adult male offspring for
an unrelated, unfamiliar adult female or their mother. The preference of adult male rats was independent
of kinship. In summary, prepubescent and adult rats do not demonstrate preference for kin vs. non-kin
(as measured by time spent near stimulus animals or who was visited first). Although kin recognition
provides a mechanism for inbreeding avoidance (Wilson, 1987), in the present study adult rats show no
evidence of inbreeding avoidance.
success in Long–Evans rats. Mating behavior was observed in sexually naïve, naturally cycling female
rats during behavioral estrous that were given the opportunity to mate with two males simultaneously.
DNA analysis of offspring born following these mating encounters was used to identify the paternity of each
pup. In order to assess the effect of mate choice during these mating encounters on reproductive success, one
male rat in each pair was categorized as the preferred mate if the female spent more time (>50%) with him
during the mating test of the present study. Furthermore, each male in the pairs was categorized as “attractive”
or “non-attractive” by computing the number of females that preferred each male across many mating
tests. Similar to results reported in Lovell et al. (2007), during 76% of these mating tests the same male rat in
each pair was preferred by different female rats. Overall attractiveness of individual male rats predicted reproductive
success in the present study. Interestingly, “attractive” males sired significantly FEWER pups
than “non-attractive” males. Neither behavioral (e.g., latency to first sexual stimulation, number of sexual
stimulations) nor physiological measures (e.g., body weight, urinary testosterone levels) of male rats predicted
their reproductive success. In conclusion, the present results indicate that certain features of some
males are more attractive to females, but attractive males are at a reproductive disadvantage (as measured
by the number of pups sired). Although basal urinary testosterone levels did not differ between males that
sired the majority of pups in a litter and males that sired few or none of the pups in a litter, aggression
and/or other physiological measures of fertility (e.g., penile reflexes) may differ between males that are attractive
to females and those that have a reproductive advantage.
Experiment 1, ovariectomized, hormone-primed rats were injected with MA (1.0 mg/kg, i.p.) or saline prior to
a test for mate choice wherein females could mate with two males simultaneously. Female rats treated with
saline returned to their preferred mate faster after receiving intromissions and visited their preferred mate at
a higher rate than their non-preferred mate. In contrast, MA-treated female rats spent a similar amount of
time with their preferred and non-preferred mate and failed to return to their preferred mate faster than to
their non-preferred mate following intromissions. Two weeks later, the females received the same drug
treatment but were tested for partner preference wherein females could spend time near a male or female
stimulus rat. All subjects spent more time near the male stimulus than the female stimulus. However, the MAtreated
rats visited the male stimulus more frequently and spent less time near the female stimulus than the
saline-treated rats. Similar to Experiment 1, female rats in Experiment 2 were tested for mate choice and then
two weeks later tested for partner preference; however, females received three daily injections of MA
(1.0 mg/kg, i.p.) or saline. Females treated chronically with MA returned to both males faster following
intromissions than females treated with saline, independent of preference (i.e., preferred mate and nonpreferred
mate). Furthermore, MA-treated rats were more likely to leave either male (i.e., preferred or nonpreferred
mate) than saline-treated rats after receiving sexual stimulation. Although MA-treated subjects
spent more time near the male stimulus than the female stimulus, they spent less time near either when
compared to saline-treated subjects. The present results demonstrate that MA affects sexual behavior in
female rats partly by increasing locomotion and partly by directly affecting sexual behavior.
escalating prevalence of obesity. We tested the hypothesis that prenatal exposure to diesel exhaust
particles (DEP), a primary component of air pollution, would prime microglia long-term, resulting in
exacerbated metabolic and affective outcomes following exposure to a high-fat diet in adulthood.
Time-mated mouse dams were intermittently exposed to respiratory instillations of either vehicle
(VEH) or DEP throughout gestation. Adult male and female offspring were then fed either a low-fat diet
(LFD) or high-fat diet (HFD) for 9 weeks. The male offspring of DEP-exposed dams exhibited exaggerated
weight gain, insulin resistance, and anxiety-like behavior on HFD compared to the male offspring of VEHexposed
dams, whereas female offspring did not differ according to prenatal treatment. Furthermore,
HFD induced evidence of macrophage infiltration of both adipose tissue and the brain in both sexes,
but these cells were more activated specifically in DEP/HFD males. DEP/HFD males also expressed markedly
higher levels of microglial/macrophage, but not astrocyte, activation markers in the hippocampus,
whereas females exhibited only a suppression of astrocyte activation markers due to HFD. In a second
experiment, DEP male offspring mounted an exaggerated peripheral IL-1b response to an LPS challenge
at postnatal day (P)30, whereas their central IL-1b response did not differ from VEH male offspring, which
is suggestive of macrophage priming due to prenatal DEP exposure. In sum, prenatal air pollution
exposure ‘‘programs’’ offspring for increased susceptibility to diet-induced metabolic, behavioral, and
neuroinflammatory changes in adulthood in a sexually dimorphic manner.
mental
health, but the mechanisms remain unclear. Increased levels of urban air pollutants interacting
with parental stress have been proposed to explain health disparities in respiratory disease,
but the impact of such interactions on mental health is unknown.
Objectives: We aimed to determine whether prenatal air pollution exposure and stress during
pregnancy act synergistically on offspring to induce a neuroinflammatory response and subsequent
neurocognitive
disorders in adulthood.
Methods: Mouse dams were intermittently exposed via oropharyngeal aspiration to diesel exhaust
particles (DEP; 50 μg × 6 doses) or vehicle throughout gestation. This exposure was combined with
standard housing or nest material restriction (NR; a novel model of maternal stress) during the last
third of gestation.
Results: Adult (postnatal day 60) offspring of dams that experienced both stressors (DEP and
NR) displayed increased anxiety, but only male offspring of this group had impaired cognition.
Furthermore, maternal DEP exposure increased proinflammatory
interleukin (IL)-1β levels
within the brains of adult males but not females, and maternal DEP and NR both decreased
anti-inflammatory IL‑10 in male, but not female, brains. Similarly, only DEP/NR males showed
increased expression of the innate immune recognition gene toll-like receptor 4 (Tlr4) and its
downstream effector, caspase-1.
Conclusions: These results show that maternal stress during late gestation increases the susceptibility
of offspring—particularly males—to the deleterious effects of prenatal
air pollutant exposure,
which may be due to a synergism of these factors acting on innate immune recognition genes and
downstream neuroinflammatory cascades within the developing brain.
over a closely related conspecific (e.g., father, mother). Preference was measured by the amount of time
spent in the vicinity of the stimulus animals as well as who was visited first. To prevent mating behavior,
stimulus animals were housed behind wire-mesh. Experiment 1 determined if adult female offspring
prefer an unrelated, unfamiliar adult male or their father. The preference of adult female rats was independent
of kinship. Experiment 2 evaluated the preference of prepubescent female and male offspring
for an unrelated, unfamiliar adult male or their father. The preference of prepubescent female and male
rats was also independent of kinship. Experiment 3 evaluated the preference of adult male offspring for
an unrelated, unfamiliar adult female or their mother. The preference of adult male rats was independent
of kinship. In summary, prepubescent and adult rats do not demonstrate preference for kin vs. non-kin
(as measured by time spent near stimulus animals or who was visited first). Although kin recognition
provides a mechanism for inbreeding avoidance (Wilson, 1987), in the present study adult rats show no
evidence of inbreeding avoidance.
success in Long–Evans rats. Mating behavior was observed in sexually naïve, naturally cycling female
rats during behavioral estrous that were given the opportunity to mate with two males simultaneously.
DNA analysis of offspring born following these mating encounters was used to identify the paternity of each
pup. In order to assess the effect of mate choice during these mating encounters on reproductive success, one
male rat in each pair was categorized as the preferred mate if the female spent more time (>50%) with him
during the mating test of the present study. Furthermore, each male in the pairs was categorized as “attractive”
or “non-attractive” by computing the number of females that preferred each male across many mating
tests. Similar to results reported in Lovell et al. (2007), during 76% of these mating tests the same male rat in
each pair was preferred by different female rats. Overall attractiveness of individual male rats predicted reproductive
success in the present study. Interestingly, “attractive” males sired significantly FEWER pups
than “non-attractive” males. Neither behavioral (e.g., latency to first sexual stimulation, number of sexual
stimulations) nor physiological measures (e.g., body weight, urinary testosterone levels) of male rats predicted
their reproductive success. In conclusion, the present results indicate that certain features of some
males are more attractive to females, but attractive males are at a reproductive disadvantage (as measured
by the number of pups sired). Although basal urinary testosterone levels did not differ between males that
sired the majority of pups in a litter and males that sired few or none of the pups in a litter, aggression
and/or other physiological measures of fertility (e.g., penile reflexes) may differ between males that are attractive
to females and those that have a reproductive advantage.
Experiment 1, ovariectomized, hormone-primed rats were injected with MA (1.0 mg/kg, i.p.) or saline prior to
a test for mate choice wherein females could mate with two males simultaneously. Female rats treated with
saline returned to their preferred mate faster after receiving intromissions and visited their preferred mate at
a higher rate than their non-preferred mate. In contrast, MA-treated female rats spent a similar amount of
time with their preferred and non-preferred mate and failed to return to their preferred mate faster than to
their non-preferred mate following intromissions. Two weeks later, the females received the same drug
treatment but were tested for partner preference wherein females could spend time near a male or female
stimulus rat. All subjects spent more time near the male stimulus than the female stimulus. However, the MAtreated
rats visited the male stimulus more frequently and spent less time near the female stimulus than the
saline-treated rats. Similar to Experiment 1, female rats in Experiment 2 were tested for mate choice and then
two weeks later tested for partner preference; however, females received three daily injections of MA
(1.0 mg/kg, i.p.) or saline. Females treated chronically with MA returned to both males faster following
intromissions than females treated with saline, independent of preference (i.e., preferred mate and nonpreferred
mate). Furthermore, MA-treated rats were more likely to leave either male (i.e., preferred or nonpreferred
mate) than saline-treated rats after receiving sexual stimulation. Although MA-treated subjects
spent more time near the male stimulus than the female stimulus, they spent less time near either when
compared to saline-treated subjects. The present results demonstrate that MA affects sexual behavior in
female rats partly by increasing locomotion and partly by directly affecting sexual behavior.