Chemosensory cues affect amygdaloid neurogenesis and alter behaviors in the socially monogamous prairie vole.

The current study examined the effects of pheromonal exposure on adult neurogenesis and revealed the role of the olfactory pathways on adult neurogenesis and behavior in the socially monogamous prairie vole (Microtus ochrogaster). Subjects were injected with a cell proliferation marker [5-bromo-2'-deoxyuridine (BrdU)] and then exposed to their own soiled bedding or bedding soiled by a same- or opposite-sex conspecific. Exposure to opposite-sex bedding increased BrdU labeling in the amygdala (AMY), but not the dentate gyrus (DG), of female, but not male, voles, indicating a sex-, stimulus-, and brain region-specific effect. The removal of the main olfactory bulbs or lesioning of the vomeronasal organ (VNOX) in females reduced BrdU labeling in the AMY and DG, and inhibited the male bedding-induced BrdU labeling in the AMY, revealing the importance of an intact olfactory pathway for amygdaloid neurogenesis. VNOX increased anxiety-like behavior and altered social preference, but it did not affect social recognition memory in female voles. VNOX also reduced the percentage of BrdU-labeled cells that co-expressed the neuronal marker TuJ1 in the AMY, but not the DG. Together, our data indicate the importance of the olfactory pathway in mediating brain plasticity in the limbic system as well as its role in behavior.

Inorganic mercury exposure in prairie voles (Microtus ochrogaster) alters the expression of toll-like receptor 4 and activates inflammatory pathways in the liver in a sex-specific manner.

Environmental exposure to mercury can cause a number of adverse effects in humans including the disruption of endocrine function that may result in sex-specific effects. The present study was designed to characterize sex-specific effects of chronic inorganic mercury exposure on toll-like receptor (TLR) 2 and TLR4 and inflammatory signaling in the liver of prairie voles (Microtus ochrogaster). Following 10 weeks of exposure to mercury via drinking water, effects on protein expression levels of TLR2 and TLR4 and the downstream p38 mitogen-activated protein kinase (p38 MAPK) and nuclear factor-kappa (NF-κB) signaling pathways were assessed. Using immunoblot analysis, we found that mercury exposure significantly enhanced the expression of TLR4 and activated p38 MAPK and NF-κB pathways in vole livers. This is the first report indicating that TLR4 may serve as a sensor for chronic mercury exposure in the liver. Further, compared to females, mercury-treated male voles exhibited significant increases in activated p38 MAPK and a greater extent of liver damage. Together, these findings establish sex-specific liver immunomodulation and cellular signaling following chronic inorganic mercury exposure. Furthermore, this study also supports the use of voles as biomarkers of environmental mercury contamination and offers a promising in vivo tool to test various therapeutic strategies for mercury detoxification.

Amphetamine effects in microtine rodents: a comparative study using monogamous and promiscuous vole species.

We compared amphetamine-induced dopamine release in the nucleus accumbens of vole species that exhibit differing mating systems to examine potential interactions between social organization and substance abuse. We found no species or regional differences in basal extracellular dopamine, however, monogamous voles had greater and longer-lasting increases in extracellular dopamine after amphetamine treatment than did promiscuous voles. We then examined whether amphetamine-induced increase in extracellular dopamine could induce pair bonds in monogamous voles. We found that, despite increasing dopamine in the nucleus accumbens, amphetamine administration did not induce pair-bonds in male prairie voles unless the animals were pretreated to preclude D1 receptor activation, which is known to inhibit pair-bond formation. These results support suggestions that social attachment and substance abuse share a common neural substrate.

Glucocorticoid receptor involvement in pair bonding in female prairie voles: the effects of acute blockade and interactions with central dopamine reward systems.

Induction of partner preferences in monogamous prairie voles (Microtus ochrogaster) was used to examine the possibility that blockade of glucocorticoid receptors may be rewarding in females of this species. We first examined the ability of either a mineralocorticoid receptor antagonist (spironolactone) or a glucocorticoid receptor antagonist (RU-486) to induce partner preferences in females. Peripheral administration of either of the antagonists was capable of inducing partner preferences, although the effective dose for RU-486 was an order of magnitude lower than that for spironolactone. We then examined a potential interaction of glucocorticoid receptor with central dopamine in pair bonding by treating females with i.c.v. dopamine receptor antagonists (haloperidol, SCH23390, or eticlopride) prior to peripheral administration of RU-486. All of the dopamine antagonists were capable of reversing the effects of glucocorticoid receptor blockade on pair bonding. These results establish the ability for acute blockade of glucocorticoid to induce pair bonds in female voles. Further, this effect appears to be mediated via an interaction with central dopamine systems. Together these findings support the possibility that, unlike other model systems, reductions in glucocorticoid receptor activity may enhance reward in female prairie voles.

Differential effects of intraspecific interactions on the striatal dopamine system in social and non-social voles.

We used in vivo microdialysis to examine the responses to intraspecific social interactions in the striatal dopamine systems of females of two vole species displaying vastly different social structures. Both highly social prairie voles and asocial meadow voles had similar increases in extracellular dopamine associated with mating. There was a species-specific effect of social condition on extracellular dihydroxyphenylacetic acid (DOPAC). Exposure to a conspecific male significantly decreased extracellular DOPAC in female prairie voles isolated for approximately 18 h during surgical recovery. Such decrease in DOPAC was not seen if females experienced continued isolation or if they were housed with a sibling during surgical recovery. No changes in extracellular DOPAC were seen in meadow voles after manipulations of social environment. Together, our data indicate that mating-associated dopamine release is independent from mating systems. However, species-specific patterns of extracellular DOPAC suggest that social isolation may be a more stressful stimulus for the social prairie vole than for the asocial meadow vole.

Differential expression of vasopressin, oxytocin and corticotrophin-releasing hormone messenger RNA in the paraventricular nucleus of the prairie vole brain following stress.

Forced swimming, as an effective stressor, has been found to facilitate the development of pair bonds in male but to interfere with this behaviour in female prairie voles (Microtus ochrogaster). In the present study, we found that forced swimming differentially influenced the expression of messenger RNA for vasopressin, oxytocin and corticotrophin-releasing hormone (CRH) in the paraventricular nucleus of the hypothalamus (PVN) in the prairie vole brain. Forced swimming did not alter vasopressin mRNA labelling, but did induce a sustained decrease in oxytocin mRNA labelling and a progressive increase in CRH mRNA labelling in the PVN. The elevated CRH mRNA labelling appeared to be due to an increased number of cells synthesizing CRH mRNA and an enhanced ability of individual cells to produce CRH mRNA. Male and female prairie voles did not differ in the vasopressin, oxytocin or CRH mRNA expression either at the basal levels or in response to swimming stress. Together, these data indicate that the hypothalamic response of vasopressin, oxytocin and CRH messenger RNAs to swimming stress is regulated by distinct transcriptional factors. In addition, it seems unlikely that these changes are involved directly in the sex differences in pair bond formation.

Vasopressin in the lateral septum regulates pair bond formation in male prairie voles (Microtus ochrogaster).

Male prairie voles (Microtus ochrogaster) form a pair bond with a female partner after mating, and this behavior is regulated by the neuropeptide vasopressin (AVP). The authors report that AVP in the lateral septum is important for pair bond formation. Administration of an AVP V1a receptor antagonist in the lateral septum blocked mating-induced pair bonding, whereas administration of AVP induced this behavior in the absence of mating. In addition, administration of an oxytocin (OT) receptor antagonist in the lateral septum also blocked pair bond formation induced by either mating or AVP administration, suggesting that the OT receptor blockade may have interfered with the AVP regulation of behavior. Together, these data provide evidence suggesting that AVP in the lateral septum regulates pair bond formation in male prairie voles and that this process requires access to both AVP and OT receptors.

Lesions of the vomeronasal organ disrupt mating-induced pair bonding in female prairie voles (Microtus ochrogaster).

The prairie vole (Microtus ochrogaster) is a highly social, monogamous species and displays pair bonding that can be assessed by the presence of selective affiliation with the familiar partner versus a conspecific stranger. In female prairie voles, exposure to a male or to male sensory cues is essential for estrus induction, and the subsequent mating facilitates pair bond formation. In the present study, we examined the role of the vomeronasal organ (VNO) in estrus induction and pair bonding in female prairie voles. VNO lesions did not alter olfaction mediated by the main olfactory system, but did prevent male-induced estrus induction. We by-passed the necessity of the VNO for estrus induction by estrogen priming the females. Despite the fact that all subjects displayed similar levels of mating, social contact and locomotor activities, VNO lesioned females failed to show mating-induced pair bonding whereas intact and sham-lesioned females displayed a robust preference for the familiar partner. Our data not only support previous findings that the VNO is important for estrus induction but also indicate that this structure is crucial for mating-induced pair bonding, suggesting an important role for the VNO in reproductive success in prairie voles.

Amino acid neurotransmitters in nucleus tractus solitarius: an in vivo microdialysis study.

Amino acid neurotransmitters in the nucleus tractus solitarius (NTS) are thought to play a key role in the mediation of visceral reflexes and glutamate has been proposed as the neurotransmitter of visceral afferent nerves projecting to this region. The present studies sought to characterize the use of in vivo microdialysis to examine extracellular fluid levels of amino acids in the NTS of anesthetized rats. Using a microdialysis probe that was 450 microns in length and a sensitive HPLC assay for amino acids, amino acids could be measured in dialysate samples collected from the NTS. Perfusion of the microdialysis probe with 60 mM K+, to elicit depolarization of nerve terminals in the vicinity of the probe, resulted in increased dialysate fluid levels of aspartate, glutamate, glycine, taurine, and GABA. In contrast, glutamine and tyrosine were decreased and other amino acids were not significantly affected. Prior removal of the ipsilateral nodose ganglion did not alter the K(+)-evoked changes in dialysate levels of any of these amino acids. Electrical stimulation of the vagus nerves, using a variety of stimulus parameters, did not significantly alter dialysate levels of glutamate or any of the other amino acids that were measured. Blockade of glutamate uptake with dihydrokainate increased dialysate levels of glutamate, aspartate, and GABA, but in the presence of dihydrokainate vagal stimulation did not alter dialysate levels of these amino acids. The results show that in vivo microdialysis can be used to examine amino acid efflux in the rat NTS and provide further evidence for amino acidergic neural transmission in the NTS. However, these studies fail to support the hypothesis that vagal afferents release glutamate or aspartate.

Measuring the therapist's impact on the patient's therapeutic progress.

This article describes methods and concepts developed by the Mount Zion Psychotherapy Research Group for empirically evaluating the pertinence of suitability of a therapist's interventions (behaviors) to a patient's particular problems, needs, and treatment goals. Intensive studies of 2 brief psychotherapy cases are presented. In these studies, patient-initiated critical incidents (tests) were identified, the case-specific accuracy of the therapist's responses to these incidents was rated, and the impact of these interventions on subsequent patient behavior was measured. The findings indicated that these patients tended to show improvement in the therapeutic process when the therapist's interventions were in accord with their particular problems and treatment goals. The application of this method to clinically relevant studies of psychotherapy is discussed.

A method for establishing reliability of statements from psychodynamic case formulations.

The authors describe a method for assessing the reliability of statements derived from psychodynamic case formulations. By reducing a narrative formulation into a series of distinct statements and rating their relevance to a particular patient, they obtained good interjudge reliabilities.

Identifying borderline hypertensives: comparative value of various blood pressure measurements.

Ambulant male military aircrew patients (n = 299) were divided into two groups based on historic evidence of normotension (N) or of untreated borderline essential hypertension (BH). All patients had their blood pressure (BP) measured under various conditions and body positions. Results were analyzed to assess the capability of each BP measurement condition to assign patients correctly to their appropriate group. Clinical BP (physician-recorded with patient seated) and orthostatic stand BP (technician-recorded) showed best sensitivity and acceptable specificity. By incorporating the results of both these measurement conditions, a predictor approximating 90% for most BH and N patients was obtained. Use of these two measurements should enable recognition of most BH patients at a single evaluation.

Blood pressure variability of the individual in orthostatic testing.

Within-subject blood pressure (BP) variability was studied in the context of orthostatic testing. Nineteen healthy men volunteered for biweekly orthostatic testing. BP's were taken on alternate minutes during 5 min of supine rest and a subsequent 5 min of quiet standing. Within-subject variance was computed for systole and diastole by protocol condition; respective variances were than pooled (i.e. averaged) across subjects. The within-subject estimate of variance for a single BP reading in either position was approximately 6 torr (i.e. 1 S.D.). This variance estimate was reduced by averaging additional BP readings from the same visit, and more so by averaging BP readings from multiple visits. These findings have use in the design of orthostatic protocols and in the interpretation of BP data derived therefrom.