Biomedical subjects

James I Koenig

Publications and source records attributed to James I Koenig.

10 recordsLinked to original sources

PubMed2006

Schizophrenia: a unique translational opportunity in behavioral neuroendocrinology.

Schizophrenia is a complex and debilitating neuropsychiatric disease in which both environmental and genetic factors contribute to the pathophysiology of the disease. Epidemiological data point to the importance of the prenatal period in the genesis of schizophrenia and suggest that environmental factors, such as stress and hormones of the hypothalamic-pituitary-adrenal axis, may establish a vulnerability to the disease. Unfortunately, the exact cause of this neurodevelopmental disease is unclear. In this review, data on the importance of gestational stress exposure to the etiology of schizophrenia-like behavioral, endocrine and molecular phenotypes will be presented and differences will be highlighted between the preparations that are commonly used in most laboratory investigations.

Animals↗

PubMed2005

Prenatal exposure to a repeated variable stress paradigm elicits behavioral and neuroendocrinological changes in the adult offspring: potential relevance to schizophrenia.

Exposure to stress during gestation induces marked changes in the behavior of the affected offspring. Examining the consequences of prenatal stress may prove useful in understanding more about the origins of schizophrenia because a number of clinical investigations have suggested that developmental insults are associated with an increased incidence of schizophrenia. The purpose of these studies is to investigate the effects of stress during gestation on the behaviors of the adult male rat offspring with an emphasis on developing a heuristic animal model of schizophrenia. Pregnant female Sprague-Dawley rats were exposed to a novel variable stress paradigm during either the second or third week of gestation. Behavioral and neuroendocrinological consequences of prenatal stress exposure were evaluated in the male offspring on postnatal day 35 or 56. Prenatal stress exposure during the third week of pregnancy caused adult male rats to exhibit prolonged elevation in plasma glucocorticoid levels following acute exposure to restraint stress indicative of diminished glucocorticoid negative feedback. Similarly, exposure to stress during the third week of pregnancy elicited an enhanced locomotor response to the psychomotor stimulant amphetamine on postnatal day 56 but not on postnatal day 35. In addition, prepulse inhibition of the acoustic startle response was diminished across a range of prepulse stimulus intensities in prenatally stressed adult male rats. Similarly, prenatally stressed rats showed evidence of a disruption in auditory sensory gating as measured by the N40 response. Taken together, these findings suggest that prenatal stress exposure significantly changed many facets of adult rat behavior. Interestingly, the behaviors that are altered have been used to validate animal models of schizophrenia and therefore, suggest that this preparation may be useful to learn more about some aspects of the pathophysiology of schizophrenia.

Age Factors↗

PubMed2005

Social interaction deficits caused by chronic phencyclidine administration are reversed by oxytocin.

Chronic administration of phencyclidine (PCP) has been advanced as a valid animal model of the social deficit symptoms of schizophrenia. In these studies, the cumulative time that male rats treated once a day for 14 days with PCP actively engaged in social behavior was decreased approximately 75% relative to saline-treated control animals. In addition, these socially impaired rats had an increase in the relative amount of noncontact interactions compared with saline-injected peers. Social behaviors were preferentially affected by PCP treatment because in two anxiety-related behavioral assays, the open field and light/dark emergence tests, there was a failure to differentiate between the PCP-treated rats and saline-injected control rats. Considering the general importance of the neuropeptides oxytocin and vasopressin in male social behaviors, studies of molecular markers related to these neuropeptides were performed. Hypothalamic oxytocin mRNA expression was significantly decreased while oxytocin receptor binding was increased in the central nucleus of the amygdala following chronic PCP treatment. Given the significance of central nucleus of the amygdala in social behavior, oxytocin was infused into the central nucleus of experimental and control male rats, and their postinfusion social interaction and open field behaviors were analyzed. A bilateral infusion of 1 mug of oxytocin into the central amygdala selectively restored the normal quantity and quality of social behavior in chronic PCP-treated male rats without altering open field behaviors. These findings suggest that deficits in the central oxytocinergic system may underlie the social impairment exhibited in this animal model of schizophrenia.

Adaptation, Physiological↗

PubMed2004

Estrogen modulates RGS9 expression in the nucleus accumbens.

Estrogen enhances psychostimulant-induced dopamine receptor-mediated behaviors. One possible mechanism for this enhancement is modulation of the expression of the regulators of G-protein signaling (RGS) proteins. Ovariectomized (OVX) rats received empty s.c. implants or implants packed with 17beta estradiol. Two weeks later the rats were given a single injection of various dopaminergic agents or saline. Estrogen administration to OVX rats selectively reduced RGS9 mRNA expression in the nucleus accumbens shell, but not core. Treating rats with D1 and D2 dopamine receptor agonists or amphetamine failed to change RGS9 mRNA expression in either OVX or OVX rats receiving estrogen. Our findings provide evidence for estrogen as a factor that enhances dopamine receptor signaling by altering RGS9 mRNA expression which could underlie gender specific patterns of psychostimulant abuse.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed2004

Regional distribution of SK3 mRNA-containing neurons in the adult and adolescent rat ventral midbrain and their relationship to dopamine-containing cells.

SK3 small conductance, calcium-activated potassium channels play an important role in regulating the activity of mesencephalic dopamine (DA) neurons. In the present series of experiments, in situ hybridization techniques were used to compare SK3 and tyrosine hydroxylase (TH) mRNA expression throughout the rostrocaudal extent of the ventral midbrain in juvenile and adult rats. SK3 mRNA was found exclusively in areas that also contained large numbers of DA neurons including the substantia nigra (SN), the ventral tegmental area, and related cell groups (VTA-A10). An anteroposterior and mediolateral gradient in SK3 mRNA hybridization was apparent in the VTA-A10 but not in the SN. Younger rats appeared to possess higher levels and less regional variation in TH and SK3 transcripts. These results are consistent with previous studies reporting differential expression of SK3 protein within the midbrain and suggest that variations in SK3 channel distribution could contribute to differences in dopamine-related functions in the rat.

Age Factors↗

PubMed2004

Centrally administered oxytocin elicits exaggerated grooming in oxytocin null mice.

Experiments were conducted to determine if the chronic absence of the neurotransmitter oxytocin (OT) in null mice resulted in alterations in the responsiveness and abundance of central OT receptors. Self-grooming elicited by intracerebroventricularly administered OT was studied as an indicator of the activation of central OT receptors and autoradiography was used to map the distribution and density of OT receptors in OT null and wild type mice. The intracerebroventricular administration of OT, but not vehicle, artificial cerebrospinal fluid (aCSF), produced a robust increase in grooming behavior in both OT null and wild type animals, P<.001. However, OT-induced grooming was significantly greater in OT null than wild type mice, P<.005. The enhanced grooming was selective to OT as indicated by the finding that grooming to intracerebroventricular arginine vasopressin (AVP) was of the same magnitude in both OT null and wild type mice. OT-induced grooming appears to be mediated through the activation of OT receptors because pretreatment of animals with an OT antagonist, Atosiban, abolished OT-induced grooming, but not AVP-induced grooming. OT receptor distribution and binding in brains of OT null and wild type mice were examined by autoradiography and were not significantly different. The results indicate that the chronic absence of OT in null mice leads to an increase in OT receptor responsiveness that contributes to the augmented grooming activity elicited by centrally administered OT.

Animals↗

PubMed2004

At issue: A model for academic/industry collaboration.

Relationships between academia and industry are increasingly intimate and commercial. While opportunities are created for each partner, there are also important conflict of interest issues. Particularly challenging is ensuring that universities maintain their traditional role in public science while partnering with a commercial entity with a tradition of proprietary science. We describe a collaboration where the interests and values of each partner were articulated in advance and conflict of interest issues were resolved before legal and business arrangements were established in a contract. We discuss the principles involved and the resolutions achieved in the hope that it may provide a useful model for addressing academic/industry scientific collaborations.

Academic Medical Centers↗

PubMed2003

Corticosterone alters N-methyl-D-aspartate receptor subunit mRNA expression before puberty.

Stress and stress hormones alter the expression of mRNA for the NR1, NR2A and NR2B subunits of the N-methyl-D-aspartate (NMDA) receptor in brain regions associated with the stress response. Early life stress contributes to the risk and pathophysiology of mental illness. Examining how stress hormones modulate NMDA receptor subunit gene expression before and after pubertal onset will further contribute to the understanding of how stress during adolescence relates to adult mental illness. Using in situ hybridization histochemistry, we measured NR1, NR2A and NR2B mRNA expression in the hippocampus and in the hypothalamic paraventricular nucleus (PVN) of rats that had undergone adrenalectomy (ADX) or sham surgery before or after puberty. Some ADX rats received corticosterone pellets that released either normal or stress levels of corticosterone for 14 days prior to sacrifice. There was a significant increase in NR1 subunit mRNA expression throughout the subfields of the hippocampus and in the PVN of ADX prepubertal rats. However, similar changes in hippocampal NR1 expression were not observed in postpubertal ADX rats. Pre- and postpubertal ADX rats implanted with a high-dose corticosterone pellet had decreased expression of PVN NR1 mRNA. Only prepubertal rats had an increase in dentate gyrus NR2A mRNA and CA3 region NR2B mRNA following high-dose replacement. These results provide evidence that glucocorticoids have differential effects on the regional expression of mRNA NMDA receptor subunits and elucidate a window during adolescence in which the NR1, NR2A and NR2B genes are responsive to glucocorticoids.

Adolescent↗

PubMed2003

Repeated variable prenatal stress alters pre- and postsynaptic gene expression in the rat frontal pole.

Exposure of pregnant women to stress during a critical period of fetal brain development is an environmental risk factor for developing schizophrenia in the adult offspring. We have applied a repeated variable stress paradigm to pregnant Sprague-Dawley rats during the last week of gestation coinciding with the second trimester in human brain development. Here we report our findings from a microarray analysis of the frontal pole of the prenatally stressed adult offspring and non-stressed adult controls complemented with measurement of plasma corticosterone levels following exposure to an acute stress. The direction of change of selected genes was confirmed by real time quantitative fluorescence PCR and in situ hybridization. The analysis revealed significant changes in genes associated with the NMDA receptor/postsynaptic density complex and the vesicle exocytosis machinery including NMDA receptor NR1 and NR2A subunits, densin-180, brain enriched guanylate kinase-associated protein, synaptosome-associated protein of 25 kDa, synaphin/complexin and vesicle-associated membrane protein 2/synaptobrevin 2. Interestingly, some of the changes in this animal preparation are analogous to changes observed in schizophrenic and bipolar patients. Our results suggest that application of a repeated variable prenatal stress paradigm during a critical period of fetal brain development reprograms the response of the hypothalamo-pituitary-adrenal axis to acute stress and results in gene expression changes that may have enduring effects on synaptic function in the offspring during adulthood.

Animals↗

PubMed2002

Glucocorticoid hormones and early brain development in schizophrenia.

While genetic factors play a role in the etiology of schizophrenia, environmental factors contribute to the etiology of the disorder as well. If a woman is exposed during the second trimester of gestation to stressors such as the death of a loved one, influenza infection, or natural and man-made disasters, her baby has an increased risk of developing schizophrenia later in life. A common mechanism may mediate the effects of these diverse risk factors: a stress response during a restricted period of gestation may affect fetal brain development and, given the appropriate genetic predisposition, result in schizophrenia in adult life. Findings in animals exposed to prenatal stress strengthen the hypothesis that exposure to high glucocorticoid levels and/or other components of the stress response increases the risk of schizophrenia. These clinical and preclinical studies could be used to develop hypotheses that could then be tested in patients with schizophrenia.

Animals↗