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1.  Arguable Assumptions, Debatable Conclusions 
Biological psychiatry  2009;67(4):e19-e23.
PMCID: PMC3784000  PMID: 20006323
2.  Early Life Stress Inhibits Expression of a Novel Innate Immune Pathway in the Developing Hippocampus 
Neuropsychopharmacology  2011;37(2):567-580.
Childhood maltreatment represents a major risk factor for the development of numerous childhood psychopathologies that in many cases linger as chronic mental illnesses in adulthood. Exposing rodents or non-human primates to early life stress increases anxiety-like behaviors and impairs cognitive function in adulthood, suggesting that animal models may provide important insights into parallel developmental processes in humans. Using an unbiased genomic screen, we found that expression of lipopolysaccharide binding protein (LBP), a member of the innate immune system, is dramatically decreased in the hippocampus of pups exposed to early life stress. LBP levels peak in the normally developing hippocampus at a period of intense synaptic pruning, during which LBP is colocalized with the synaptic marker PSD95 and is found in close proximity to processes of microglia cells. Expression of LBP declines to low levels seen in adulthood at around postnatal day 30. Importantly, 30-day-old LBP knockout (k.o.) mice show increased spine density and abnormal spine morphology, suggesting that peak levels of LBP during the second and third weeks of life are necessary for normal synaptic pruning in the hippocampus. Finally, LBP k.o. mice show impaired hippocampal-dependent memory and increased anxiety-like behaviors in a manner that resembles that seen in animals exposed to early life stress. These findings describe a novel role for LBP in normal hippocampal development and raise the possibility that at least some of the behavioral sequelae of early life stress are mediated by reduced expression of LBP during a critical period of neurodevelopment.
PMCID: PMC3242319  PMID: 21993208
lipopolysaccharide binding protein; early life stress; mice; neurodevelopment; innate immune system; microarray; development/developmental disorders; animal models; biological psychiatry; molecular & cellular neurobiology; lipopolysaccharide binding protein; early life stress; mice; neurodevelopment; innate immune system
3.  New Frontiers in Animal Research of Psychiatric Illness 
Alterations in neurodevelopment are thought to modify risk of numerous psychiatric disorders, including schizophrenia, autism, ADHD, mood and anxiety disorders, and substance abuse. However, little is known about the cellular and molecular changes that guide these neurodevelopmental changes and how they contribute to mental illness. In this review, we suggest that elucidating this process in humans requires the use of model organisms. Furthermore, we advocate that such translational work should focus on the role that genes and/or environmental factors play in the development of circuits that regulate specific physiological and behavioral outcomes in adulthood. This emphasis on circuit development, as a fundamental unit for understanding behavior, is distinct from current approaches of modeling psychiatric illnesses in animals in two important ways. First, it proposes to replace the diagnostic and statistical manual of mental disorders (DSM) diagnostic system with measurable endophenotypes as the basis for modeling human psychopathology in animals. We argue that a major difficulty in establishing valid animal models lies in their reliance on the DSM/International Classification of Diseases conceptual framework, and suggest that the Research Domain Criteria project, recently proposed by the NIMH, provides a more suitable system to model human psychopathology in animals. Second, this proposal emphasizes the developmental origin of many (though clearly not all) psychiatric illnesses, an issue that is often glossed over in current animal models of mental illness. We suggest that animal models are essential to elucidate the mechanisms by which neurodevelopmental changes program complex behavior in adulthood. A better understanding of this issue, in animals, is the key for defining human psychopathology, and the development of earlier and more effective interventions for mental illness.
PMCID: PMC3337084  PMID: 22231804
Animal models; Mental illness; Neurodevelopment; Endophenotype; RDoC
4.  Affiliative behavior requires juvenile, but not adult neurogenesis 
The capacity to interact with conspecifics is essential for stable social networks, reproduction, and survival in mammals. In rodents, social exploration and play behavior increase during the juvenile period suggesting that this timeframe represents an important window for socialization. However, the cellular and molecular mechanisms necessary to support this developmental process have not been elucidated. Neurogenesis during the juvenile period, like that in adults, is mainly confined to the subgranular and subventricular zones. Nevertheless, the levels of neurogenesis are significantly higher during the juvenile period suggesting unique functions not shared with adult neurogenesis. Here we use a transgenic mouse approach that allows for ablation of neurogenesis during different developmental phases. We find that ablating neurogenesis during either juvenile or adult phases altered anxiety and memory in adult female mice, demonstrating an age-independent function of new neurons for certain behaviors. Blocking neurogenesis during the juvenile period resulted in a profound impairment in the ability of these mice to interact with other adult females or to retrieve pups, without causing gross olfactory deficits. Interestingly, ablating neurogenesis in adult females had no effect on these social behaviors. This work defines a novel role for juvenile neurogenesis in establishing brain circuits necessary for socialization, and demonstrates that juvenile- and adult-neurogenesis make different contributions to social competency in adult female mice. Additional work is needed to determine whether ablation of juvenile neurogenesis in the subgranular zone and/or the subventricular zone is responsible for the social abnormalities seen after global elimination of juvenile neurogenesis.
PMCID: PMC3204413  PMID: 21976519
5.  Early-life Stress, Corticotropin-Releasing Factor, and Serotonin Transporter Gene: A Pilot Study 
Psychoneuroendocrinology  2010;36(2):289-293.
Recent studies have indicated a gene by environment interaction between serotonin transporter gene (5-HTTLPR) polymorphism and childhood abuse on depressive symptoms. In addition, persistent elevation of cerebrospinal fluid (CSF) corticotropin-releasing factor (CRF) concentrations following early-life adversity has been posited to underlie the subsequent development of major depression. This pilot study tested the hypothesis that elevations of juvenile CSF CRF concentrations are, in part, determined by an interaction between polymorphisms of the 5-HTTLPR and early-life stress. Nine juvenile male bonnet macaques (Macaca radiata) had been raised under variable foraging demand (VFD) conditions, a nonhuman primate model of early-life stress, whereas nine subjects were normatively raised under LFD (low foraging demand) conditions. Genotyping revealed that four (44.4%) of the VFD-reared monkeys possessed at least one “s” allele whereas five VFD monkeys were of the l/l genotype. Of the nine LFD subjects, two (22%) had the s/l genotype and seven had the l/l genotype. A “juvenile” CSF sample was obtained at approximately three years of age. CSF CRF concentrations were elevated specifically in the VFD “s/s” and “s/l” allele group in comparison to each of the remaining three groups, indicating a gene by environment (GxE) interaction.
PMCID: PMC3017732  PMID: 20692103
Nonhuman primates; corticotropin-releasing hormone; early-life stress; serotonin transporter gene; major depression; anxiety disorders; gene by environment interaction
6.  The role of early life stress in development of the anterior limb of the internal capsule in non-human primates 
Neuroscience letters  2010;480(2):93-96.
Deep brain stimulation (DBS) of the anterior limb of the internal capsule (ALIC) may be effective in treating depression. Parental verbal abuse has been linked to decreased fractional anisotropy (FA) of white matter and reduced FA correlated with depression and anxiety scores. Utilizing a nonhuman primate model of mood and anxiety disorders following disrupted mother-infant attachment, we examined whether adverse rearing conditions lead to white matter impairment of the ALIC.
We examined white matter integrity using Diffusion Tensor Imaging (DTI) on a 3T-MRI. Twenty-one adult male Bonnet macaques participated in this study: 12 were reared under adverse [variable foraging demand (VFD)] conditions whereas 9 were reared under normative conditions. We examined ALIC, posterior limb of the internal capsule (PLIC) and occipital white matter.
VFD rearing was associated with significant reductions in FA in the ALIC with no changes evident in the PLIC or occipital cortex white matter.
Adverse rearing in monkeys persistently impaired frontal white matter tract integrity, a novel substrate for understanding affective susceptibility.
PMCID: PMC2951885  PMID: 20541590
Diffusion tensor imaging; fractional anisotropy; white matter integrity; variable foraging demand
7.  Early life stress increases anxiety-like behavior in Balbc mice despite a compensatory increase in levels of postnatal maternal care 
Hormones and behavior  2010;57(4-5):396-404.
A better understanding of the molecular and cellular mechanisms by which early life stress (ELS) modifies brain development and adult behavior is necessary for diagnosing and treating psychopathology associated with exposure to ELS. For historical reasons most of the work in rodents has been done in rats and attempts to establish robust and reproducible paradigms in the mouse have proven to be challenging. Here we show that under normal rearing conditions, increased levels of postnatal maternal care are associated with a decrease in anxiety-like behavior in BALB/cByj offspring. Brief daily pup-dam separation (BDS) during the postnatal period was associated with increased postnatal maternal care but was surprisingly associated with increased anxiety-like behavior in adult offspring, providing the first example in which offspring receiving higher levels of postnatal maternal care are more anxious in adulthood. Plasma corticosterone levels were elevated in BDS pups even three hours after the pups were reunited with the dam, suggesting that this paradigm represents a form of early life stress. We also show that levels of total RNA and DNA in the hippocampus reach a peak at postnatal day 14 and that exposure to BDS seems to inhibit this developmental growth spurt. We propose that exposure to stress during the postnatal period overrides the ability of high levels of postnatal maternal care to program anxiety-like behavior by inhibiting the normal growth spurt that characterizes this period.
PMCID: PMC2849915  PMID: 20096699
maternal care; early life stress; handling; neurodevelopment; mice; anxiety; Hippocampus
8.  The Silent Epidemic of Neurodevelopmental Injuries 
Biological psychiatry  2009;66(7):624-626.
PMCID: PMC2840038  PMID: 19747590

Results 1-8 (8)