ARNT2 acts as the dimerization partner of SIM1 for the development of the hypothalamus. (1/68)

One major function of the hypothalamus is to maintain homeostasis by modulating the secretion of pituitary hormones. The paraventricular (PVN) and supraoptic (SON) nuclei are major integration centers for the output of the hypothalamus to the pituitary. The bHLH-PAS transcription factor SIM1 is crucial for the development of several neuroendocrine lineages within the PVN and SON. bHLH-PAS proteins require heterodimerization for their function. ARNT, ARNT2, and BMAL1 are the three known general heterodimerization partners for bHLH-PAS proteins. Here, we provide evidence that Sim1 and Arnt2 form dimers in vitro, that they are co-expressed in the PVN and SON, and that their loss of function affects the development of the same sets of neuroendocrine cell types within the PVN and SON. Together, these results implicate ARNT2 as the in vivo dimerization partner of SIM1 in controlling the development of these neuroendocrine lineages.  (+info)

A cholecystokinin-mediated pathway to the paraventricular thalamus is recruited in chronically stressed rats and regulates hypothalamic-pituitary-adrenal function. (2/68)

Chronic stress alters hypothalamic-pituitary-adrenal (HPA) responses to acute, novel stress. After acute restraint, the posterior division of the paraventricular thalamic nucleus (pPVTh) exhibits increased numbers of Fos-expressing neurons in chronically cold-stressed rats compared with stress-naive controls. Furthermore, lesions of the PVTh augment HPA activity in response to novel restraint only in previously stressed rats, suggesting that the PVTh is inhibitory to HPA activity but that inhibition occurs only in chronically stressed rats. In this study, we further examined pPVTh functions in chronically stressed rats. We identified afferent projections to the pPVTh using injection of the retrograde tracer fluorogold. Of the sites containing fluorogold-labeled cells, neurons in the lateral parabrachial, periaqueductal gray, and dorsal raphe containing fluorogold also expressed cholecystokinin (CCK) mRNA. We then examined whether these CCKergic inputs to the pPVTh were involved in HPA responses to acute, novel restraint after chronic stress. We injected the CCK-B receptor antagonist PD 135,158 into the PVTh before restraint in control and chronically cold-stressed rats. ACTH responses to restraint stress were augmented by PD 135,158 only in chronically stressed rats but not in controls. In addition, CCK-B receptor mRNA expression in the pPVTh was not altered by chronic cold stress. We conclude that previous chronic stress specifically facilitates the release of CCK into the pPVTh in response to acute, novel stress. The CCK is probably secreted from neurons in the lateral parabrachial, the periaqueductal gray, and/or the dorsal raphe nuclei. Acting via CCK-B receptors in pPVTh, CCK then constrains facilitated ACTH responses to novel stress in chronically stressed but not naive rats. These results demonstrate clearly that chronic stress recruits a new set of pathways that modulate HPA responsiveness to a novel stress.  (+info)

The murine Otp homeobox gene plays an essential role in the specification of neuronal cell lineages in the developing hypothalamus. (3/68)

Hypothalamic nuclei, including the anterior periventricular (aPV), paraventricular (PVN), and supraoptic (SON) nuclei strongly express the homeobox gene Orthopedia (Otp) during embryogenesis. Targeted inactivation of Otp in the mouse results in the loss of these nuclei in the homozygous null neonates. The Otp null hypothalamus fails to secrete neuropeptides somatostatin, arginine vasopressin, oxytocin, corticotropin-releasing hormone, and thyrotropin-releasing hormone in an appropriate spatial and temporal fashion, and leads to the death of Otp null pups shortly after birth. Failure to produce these neuropeptide hormones is evident prior to E15.5, indicating a failure in terminal differentiation of the aPV/PVN/SON neurons. Absence of elevated apoptotic activity, but reduced cell proliferation together with the ectopic activation of Six3 expression in the presumptive PVN, indicates a critical role for Otp in terminal differentiation and maturation of these neuroendocrine cell lineages. Otp employs distinct regulatory mechanisms to modulate the expression of specific molecular markers in the developing hypothalamus. At early embryonic stages, expression of Sim2 is immediately downregulated as a result of the absence of Otp, indicating a potential role for Otp as an upstream regulator of Sim2. In contrast, the regulation of Brn4 which is also expressed in the SON and PVN is independent of Otp function. Hence no strong evidence links Otp and Brn4 in the same regulatory pathway. The involvement of Otp and Sim1 in specifying specific hypothalamic neurosecretory cell lineages is shown to operate via distinct signaling pathways that partially overlap with Brn2.  (+info)

Refractoriness to melatonin occurs independently at multiple brain sites in Siberian hamsters. (4/68)

The mid-winter development of refractoriness to melatonin (Mel) triggers recrudescence of the atrophied reproductive apparatus of rodents. As a consequence, over-wintering animals become reproductively competent just before the onset of spring conditions favorable for breeding. The neural target tissues that cease to respond to winter Mel signals have not been identified. We now report that the suprachiasmatic nucleus of the hypothalamus, which contains the principal circadian clock, and the reuniens and paraventricular nuclei of the thalamus, each independently becomes refractory to melatonin. Small implants of Mel that were left in place for 40 wk and that act locally on these brain nuclei, induced testicular regression within 6 wk in male Siberian hamsters; 12 wk later Mel implants no longer suppressed reproduction and gonadal recrudescence ensued. Hamsters that were then given a systemic Mel infusion s.c. immediately initiated a second gonadal regression, implying that neurons at each site become refractory to Mel without compromising responsiveness of other Mel target tissues. Refractoriness occurs locally and independently at each neural target tissue, rather than in a separate "refractoriness" substrate. Restricted, target-specific actions of Mel are consistent with the independent regulation by day length of the several behavioral and physiological traits that vary seasonally in mammals.  (+info)

Passive movements of the head do not abolish anticipatory firing properties of head direction cells. (5/68)

Neurons in the anterior dorsal thalamic nucleus (ADN) of the rat selectively discharge in relation to the animal's head direction (HD) in the horizontal plane. Temporal analyses of cell firing properties reveal that their discharge is optimally correlated with the animal's future directional heading by approximately 24 ms. Among the hypotheses proposed to explain this property is that ADN HD cells are informed of future head movement via motor efference copy signals. One prediction of this hypothesis is that when the rat's head is moved passively, the anticipatory time interval (ATI) will be attenuated because the motor efference signal reflects only the active contribution to the movement. The present study tested this hypothesis by loosely restraining the animal and passively rotating it through the cell's preferred direction. Contrary to our prediction, we found that ATI values did not decrease during passive movement but in fact increased significantly. HD cells in the postsubiculum did not show the same effect, suggesting independence between the two sites with respect to anticipatory firing. We conclude that it is unlikely that a motor efference copy signal alone is responsible for generating anticipatory firing in ADN HD cells.  (+info)

Perception, action, and Roelofs effect: a mere illusion of dissociation. (6/68)

A prominent and influential hypothesis of vision suggests the existence of two separate visual systems within the brain, one creating our perception of the world and another guiding our actions within it. The induced Roelofs effect has been described as providing strong evidence for this perception/action dissociation: When a small visual target is surrounded by a large frame positioned so that the frame's center is offset from the observer's midline, the perceived location of the target is shifted in the direction opposite the frame's offset. In spite of this perceptual mislocalization, however, the observer can accurately guide movements to the target location. Thus, perception is prone to the illusion while actions seem immune. Here we demonstrate that the Roelofs illusion is caused by a frame-induced transient distortion of the observer's apparent midline. We further demonstrate that actions guided to targets within this same distorted egocentric reference frame are fully expected to be accurate, since the errors of target localization will exactly cancel the errors of motor guidance. These findings provide a mechanistic explanation for the various perceptual and motor effects of the induced Roelofs illusion without requiring the existence of separate neural systems for perception and action. Given this, the behavioral dissociation that accompanies the Roelofs effect cannot be considered evidence of a dissociation of perception and action. This indicates a general need to re-evaluate the broad class of evidence purported to support this hypothesized dissociation.  (+info)

Involvement of thalamic paraventricular nucleus in the anticipatory reaction under food restriction in the rat. (7/68)

To investigate which brain regions are involved in the anticipatory activity in rats restricted feeding for 2 hr, we examined c-Fos expression before and after feeding. Only the thalamic paraventricular nucleus (tPVN) showed c-Fos expression before feeding than after feeding. After the anticipatory locomotor activity rhythm was established, lesioning the tPVN attenuated this rhythm, but not the light-dark entrained rhythm. The anticipatory increase of blood corticosterone levels was not established in long-term tPVN-lesioned rats. These results suggest that the tPVN is involved in the expression of anticipatory reactions under a food-restricted regimen.  (+info)

Suppression of vasoactive intestinal polypeptide in the suprachiasmatic nucleus leads to aging-like alterations in cAMP rhythms and activation of gonadotropin-releasing hormone neurons. (8/68)

Input from the suprachiasmatic nucleus (SCN) to gonadotropin-releasing hormone (GnRH) neurons is critical to the occurrence of regular cyclic GnRH secretion. It is thought that an essential neuropeptide in the SCN that communicates this cyclic information to GnRH neurons is vasoactive intestinal polypeptide (VIP) and that it may act through cAMP. We tested the hypothesis that (1) aging involves a blunting of cAMP diurnal rhythmicity in the SCN; (2) administration of antisense oligonucleotides (anti-oligos) against VIP, which produces an aging-like pattern in VIP, would lead to an aging-like suppression of cAMP; and (3) this in turn would lead to inhibition of the steroid-induced activation of GnRH neurons. We measured cAMP concentrations in the SCN and rostral preoptic nucleus throughout the day in young and middle-aged rats that were ovariectomized (OVX) or OVX and treated with estradiol. Our results show that cAMP concentrations exhibit a diurnal rhythm in young rats, and that this rhythm is totally abolished by the time rats are middle age. Administration of antisense oligonucleotides against VIP or random oligos suppresses VIP concentrations and abolishes the cAMP rhythm, leading to significantly reduced activation of GnRH neurons. Together, these findings strongly suggest that the SCN conveys diurnal information to GnRH neurons by driving VIP-dependent cAMP rhythms. In addition, aging involves deterioration in this VIP-driven rhythmicity, which impacts the ability of steroids to induce GnRH neuronal activation.  (+info)