Medial prefrontal cortex control of the paraventricular hypothalamic nucleus response to psychological stress : possible role of the bed nucleus of the stria terminalis

The medial prefrontal cortex (mPFC) has been strongly implicated in control of the paraventricular nucleus of the hypothalamus (PVN) response to stress. Because of the paucity of direct projections from the mPFC to the PVN, we sought to investigate possible brain regions that might act as a relay between the two during psychological stress. Bilateral ibotenic acid lesions of the rat mPFC enhanced the number of Fos-immunoreactive cells seen in the PVN after exposure to the psychological stressor, air puff. Altered neuronal recruitment was seen in only one of the candidate relay populations examined, the ventral bed nucleus of the stria terminalis (vBNST). Furthermore, bilateral ibotenic acid lesions of the BNST caused a significant attenuation of the PVN response to air puff. To better characterize the structural relationships between the mPFC and PVN, retrograde tracing studies were conducted examining Fos expression in cells retrogradely labeled with cholera toxin b subunit (CTb) from the PVN and the BNST. Results obtained were consistent with an important role for both the mPFC and BNST in the mpPVN CRF cell response to air puff. We suggest a set of connections whereby a direct PVN projection from the ipsilateral vBNST is involved in the mpPVN response to air puff and this may, in turn, be modulated by an indirect projection from the mPFC to the BNST.

Sexual selection predicts brain structure in dragon lizards

Phenotypic traits such as ornaments and armaments are generally shaped by sexual selection, which often favours larger and more elaborate males compared to females. But can sexual selection also influence the brain? Previous studies in vertebrates report contradictory results with no consistent pattern between variation in brain structure and the strength of sexual selection. We hypothesize that sexual selection will act in a consistent way on two vertebrate brain regions that directly regulate sexual behaviour: the medial preoptic nucleus (MPON) and the ventromedial hypothalamic nucleus (VMN). The MPON regulates male reproductive behaviour whereas the VMN regulates female reproductive behaviour and is also involved in male aggression. To test our hypothesis, we used high-resolution magnetic resonance imaging combined with traditional histology of brains in 14 dragon lizard species of the genus Ctenophorus that vary in the strength of precopulatory sexual selection. Males belonging to species that experience greater sexual selection had a larger MPON and a smaller VMN. Conversely, females did not show any patterns of variation in these brain regions. As the volumes of both these regions also correlated with brain volume (BV) in our models, we tested whether they show the same pattern of evolution in response to changes in BV and found that the do. Therefore, we show that the primary brain nuclei underlying reproductive behaviour in vertebrates can evolve in a mosaic fashion, differently between males and females, likely in response to sexual selection, and that these same regions are simultaneously evolving in concert in relation to overall brain size.

Hypothalamic paraventricular nucleus neurons regulate medullary catecholamine cell responses to restraint stress

Both physical and psychological stressors recruit catecholamine cells (CA) located in the ventrolateral medulla (VLM) and the nucleus of the solitary tract (NTS). In the case of physical stressors, this effect is initiated by signals that first access the central nervous system at or below the level of the medulla. For psychological stressors, however, CA cell recruitment depends on higher structures within the neuraxis. Indeed, we have recently provided evidence of a pivotal role for the medial amygdala (MeA) in this regard, although such a role must involve a relay, as MeA neurons do not project directly to the medulla. However, some of the MeA neurons that respond to psychological stress have been found to project to the hypothalamic paraventricular nucleus (PVN), a structure that provides significant input to the medulla. To determine whether the PVN might regulate medullary CA cell responses to psychological stress, animals were prepared with unilateral injections of the neurotoxin ibotenic acid into the PVN (Experiment 1), or with unilateral injections of the retrograde tracer wheat germ agglutinin-gold (WGA-Au) into the CA cell columns of the VLM or NTS (Experiment 2). Seven days later, animals were subjected to a psychological stressor (restraint; 15 minutes), and their brains were subsequently processed for Fos plus appropriate cytoplasmic markers (Experiment 1), or Fos plus WGA-Au (Experiment 2). PVN lesions significantly suppressed the stress-related induction of Fos in both VLM and NTS CA cells, whereas tracer deposits in the VLM or NTS retrogradely labeled substantial numbers of PVN cells that were also Fos-positive after stress. Considered in concert with previous results, these data suggest that the activation of medullary CA cells in response to psychological stress may involve a critical input from the PVN.

Descending pathways from the paraventricular nucleus contribute to the recruitment of brainstem nuclei following a systemic immune challenge

Hypothalamic nuclei, particularly the paraventricular nuclei (PVN), are important brain sites responsible for central nervous system responses during an immune challenge. The brainstem catecholamine cells of the nucleus tractus solitarius (NTS) and ventrolateral medulla (VLM) have been shown to play critical roles in relaying systemic immune signals to the PVN. However, whilst it is well recognised that PVN divisions also innervate the NTS and VLM, it is not known whether descending PVN pathways can modulate the recruitment of brainstem cells during an immune challenge. Using systemic administration of the proinflammatory cytokine interleukin-1β, in combination with Fos immunolabelling, we firstly investigated the effect of PVN lesions on NTS and VLM catecholamine and non-catecholamine cell responses. We found that ibotenic acid lesions of the PVN significantly reduced numbers of Fos-positive non-catecholamine, noradrenergic and adrenergic cells observable in the VLM and NTS after interleukin-1β administration. We then investigated the origins of descending inputs to the VLM and NTS, activated by systemic interleukin-1β, by mapping the distribution of Fos-positive retrogradely-labelled cells in divisions of the PVN after iontophoretically depositing choleratoxin-b subunit into the NTS or VLM one week prior to interleukin-1β administration. We found that, after either NTS or VLM deposits, the majority of retrogradely-labelled Fos-positive cells activated by interleukin-1β were localised in the medial and lateral parvocellular PVN divisions. Retrogradely-labelled Fos-positive cells were also observed in the NTS after VLM deposits, and in the VLM after NTS tracer deposits, suggesting reciprocal communication between these two nuclei after systemic interleukin-1β. Thus the present study shows that the PVN has the capacity to modulate NTS and VLM responses after an immune challenge and that these may result from descending projections arising in the medial and lateral PVN divisions. These findings suggest that central nervous system responses to an immune challenge are likely to involve complex reciprocal connections between the PVN and the brainstem as well as between brainstem nuclei themselves.

Differential involvement of rat medial prefrontal cortex dopamine receptors in modulation of hypothalamic- pituitary-adrenal axis responses to different stressors

Recent investigations have implicated the medial prefrontal cortex (mPFC) in modulation of subcortical pathways that contribute to the generation of behavioural, autonomic and endocrine responses to stress. However, little is known of the mechanisms involved. One of the key neurotransmitters involved in mPFC function is dopamine, and we therefore aimed, in this investigation, to examine the role of mPFC dopamine in response to stress in Wistar rats. In this regard, we infused dopamine antagonists SCH23390 or sulpiride into the mPFC via retrodialysis. We then examined changes in numbers of cells expressing the c-fos immediate-early gene protein product, Fos, in subcortical neuronal populations associated with regulation of hypothalamic-pituitary-adrenal (HPA) axis stress responses in response to either of two stressors; systemic injection of interleukin-1β, or air puff. The D1 antagonist, SCH23390, and the D2 antagonist, sulpiride, both attenuated expression of Fos in the medial parvocellular hypothalamic paraventricular nucleus (mpPVN) corticotropin-releasing factor cells at the apex of the HPA axis, as well as in most extra-hypothalamic brain regions examined in response to interleukin-1β. By contrast, SCH23390 failed to affect Fos expression in response to air puff in any brain region examined, while sulpiride resulted in an attenuation of the air puff-induced response in only the mpPVN and the bed nucleus of the stria terminalis. These results indicate that the mPFC differentially processes the response to different stressors and that the two types of dopamine receptor may have different roles.

Dorsal and ventral medullary catecholamine cell groups contribute differentially to systemic interleukin-1beta-induced hypothalamic pituitary adrenal axis responses

Medial parvocellular paraventricular corticotropin-releasing hormone (mPVN CRH) cells are critical in generating hypothalamic-pituitary-adrenal (HPA) axis responses to systemic interleukin-1beta (IL-1beta). However, although it is understood that catecholamine inputs are important in initiating mPVN CRH cell responses to IL-1beta, the contributions of distinct brainstem catecholamine cell groups are not known. We examined the role of nucleus tractus solitarius (NTS) and ventrolateral medulla (VLM) catecholamine cells in the activation of mPVN CRH, hypothalamic oxytocin (OT) and central amygdala cells in response to IL-1beta (1 microg/kg, i.a.). Immunolabelling for the expression of c-fos was used as a marker of neuronal activation in combination with appropriate cytoplasmic phenotypic markers. First we confirmed that PVN 6-hydroxydopamine lesions, which selectively depleted catecholaminergic terminals, significantly reduced IL-1beta-induced mPVN CRH cell activation. The contribution of VLM (A1/C1 cells) versus NTS (A2 cells) catecholamine cells to mPVN CRH cell responses was then examined by placing ibotenic acid lesions in either the VLM or NTS. The precise positioning of these lesions was guided by prior retrograde tracing studies in which we mapped the location of IL-1beta-activated VLM and NTS cells that project to the mPVN. Both VLM and NTS lesions reduced the mPVN CRH and OT cell responses to IL-1beta. Unlike VLM lesions, NTS lesions also suppressed the recruitment of central amygdala neurons. These studies provide novel evidence that both the NTS and VLM catecholamine cells have important, but differential, contributions to the generation of IL-1beta-induced HPA axis responses.

Evidence that the bed nucleus of the stria terminalis contributes to the modulation of hypophysiotropic corticotropin-releasing factor cell responses to systemic interleukin-1β

Systemic infection activates the hypothalamic-pituitary-adrenal (HPA) axis, and brainstem catecholamine cells have been shown to contribute to this response. However, recent work also suggests an important role for the central amygdala (CeA). Because direct connections between the CeA and the hypothalamic apex of the HPA axis are minimal, the present study investigated whether the bed nucleus of the stria terminalis (BNST) might act as a relay between them. This was done by using an animal model of acute systemic infection involving intravascular delivery of the proinflammatory cytokine interleukin-1β (IL-1β, 1 μg/kg). Unilateral ibotenic acid lesions encompassing the ventral BNST significantly reduced both IL-1β-induced increases in Fos immunoreactivity in corticotropin-releasing factor (CRF) cells of the hypothalamic paraventricular nucleus (PVN) and corresponding increases in adrenocorticotropic hormone (ACTH) secretion. Similar lesions had no effect on CRF cell responses to physical restraint, suggesting that the effects of BNST lesions were not due to a nonspecific effect on stress responses. In further studies, we examined the functional connections between PVN, BNST, and CeA by combining retrograde tracing with mapping of IL-1β-induced increases in Fos in BNST and CeA cells. In the case of the BNST, these studies showed that systemic IL-1β administration recruits ventral BNST cells that project directly to the PVN. In the case of the CeA, the results obtained were consistent with an arrangement whereby lateral CeA cells recruited by systemic IL-1β could regulate the activity of medial CeA cells projecting directly to the BNST. In conclusion, the present findings are consistent with the hypothesis that the BNST acts as a relay between the CeA and PVN, thereby contributing to CeA modulation of hypophysiotropic CRF cell responses to systemic administration of IL-1β.

Medullary neurones regulate hypothalamic corticotropin-releasing factor cell responses to an emotional stressor

Hypothalamic–pituitary–adrenal axis activation is a hallmark of the stress response. In the case of physical stressors, there is considerable evidence that medullary catecholamine neurones are critical to the activation of the paraventricular nucleus corticotropin-releasing factor cells that constitute the apex of the hypothalamic–pituitary–adrenal axis. In contrast, it has been thought that hypothalamic–pituitary–adrenal axis responses to emotional stressors do not involve brainstem neurones. To investigate this issue we have mapped patterns of restraint-induced neuronal c-fos expression in intact animals and in animals prepared with either paraventricular nucleus-directed injections of a retrograde tracer, lesions of paraventricular nucleus catecholamine terminals, or lesions of the medulla corresponding to the A1 or A2 noradrenergic cell groups. Restraint-induced patterns of neuronal activation within the medulla of intact animals were very similar to those previously reported in response to physical stressors, including the fact that most stressor-responsive, paraventricular nucleus-projecting cells were certainly catecholaminergic and probably noradrenergic. Despite this, the destruction of paraventricular nucleus catecholamine terminals with 6-hydroxydopamine did not alter corticotropin-releasing factor cell responses to restraint. However, animals with ibotenic acid lesions encompassing either the A1 or A2 noradrenergic cell groups displayed significantly suppressed corticotropin-releasing factor cell responses to restraint. Notably, these medullary lesions also suppressed neuronal responses in the medial amygdala, an area that is now considered critical to hypothalamic–pituitary–adrenal axis responses to emotional stressors and that is also known to display a significant increase in noradrenaline turnover during restraint.

We conclude that medullary neurones influence corticotropin-releasing factor cell responses to emotional stressors via a multisynaptic pathway that may involve a noradrenergic input to the medial amygdala. These results overturn the idea that hypothalamic–pituitary–adrenal axis response to emotional stressors can occur independently of the brainstem.

Underlying neurobiology and clinical correlates of mania status after subthalamic nucleus deep brain stimulation in Parkinson's Disease : a review of the literature

Deep brain stimulation (DBS) is a novel and effective surgical intervention for refractory Parkinson's disease (PD). The authors review the current literature to identify the clinical correlates associated with subthalamic nucleus (STN) DBS-induced hypomania/mania in PD patients. Ventromedial electrode placement has been most consistently implicated in the induction of STN DBS-induced mania. There is some evidence of symptom amelioration when electrode placement is switched to a more dorsolateral contact. Additional clinical correlates may include unipolar stimulation, higher voltage (>3 V), male sex, and/or early-onset PD. STN DBS-induced psychiatric adverse events emphasize the need for comprehensive psychiatric presurgical evaluation and follow-up in PD patients. Animal studies and prospective clinical research, combined with advanced neuroimaging techniques, are needed to identify clinical correlates and underlying neurobiological mechanisms of STN DBS-induced mania. Such working models would serve to further our understanding of the neurobiological underpinnings of mania and contribute valuable new insight toward development of future DBS mood-stabilization therapies.

Elevated hypothalamic beacon gene expression in Psammomys obesus prone to develop obesity and type 2 diabetes

Objective: To investigate hypothalamic beacon gene expression at various developmental stages in genetically selected diabetes-resistant and diabetes-prone Psammomys obesus. In addition, effects of dietary energy composition on beacon gene expression were investigated in diabetes-prone P. obesus. Methods: Hypothalamic beacon gene expression was measured using TaqmanÔ fluorogenic PCR in 4-, 8- and 16-week-old animals from each genetically selected line. Results: Expression of beacon was elevated in the diabetes-prone compared with diabetes-resistant P. obesus at 4 weeks of age despite no difference in body weight between the groups. At 8 weeks of age, hypothalamic beacon gene expression was elevated in diabetes-prone animals fed a high-energy diet, and was correlated with serum insulin concentration. Conclusion: P. obesus with a genetic predisposition for the development of obesity and type 2 diabetes have elevated hypothalamic beacon gene expression at an early age. Overexpression of beacon may contribute to the development of obesity and insulin resistance in these animals.

Identification of hypothalamic genes implicated in the development of obesity in Psammomys obesus using differential display PCR

The hypothalamus is a key central controller of energy homeostasis and is the source and/or site of action of many neuropeptides involved in this process. The aim of this study was to isolate hypothalamic genes differentially expressed between lean and obese Psammomys obesus, a polygenic animal model of obesity and type 2 diabetes. Differential display PCR was used to compare hypothalamic gene expression profiles of lean and healthy, obese and hyperinsulinemic, and obese, diabetic P. obesus in both the fed and fasted states. We conducted differential display with 180 separate primer combinations to amplify approximately 9000 expressed transcripts. Sixty differentially expressed bands were excised. Taqman PCR was performed on 36 of these transcripts to confirm differential gene expression in a larger sample population. Of these 36 transcripts, 9 showed homology to known genes, and 27 were considered to be novel sequences. Gene expression profiles for two of these genes are presented here. In conclusion, differential display PCR was successfully used to isolate several transcripts that may be involved in the central regulation of energy balance. We are currently conducting numerous studies to further investigate the role of these genes in the development of obesity in P. obesus.