Hypocretin in locus coeruleus and dorsal raphe nucleus mediates inescapable footshock stimulation (IFS)-induced REM sleep alteration

Hypocretin (hcrt) is a stress-reacting neuropeptide mediating arousal and energy homeostasis. An inescapable footshock stimulation (IFS) could initiate the hcrt release from the lateral hypothalamus (LHA) and suppresses rapid eye movement (REM) sleep in rodents. However, the effects of the IFS-induced hcrts on REM-off nuclei, the locus coeruleus (LC) and dorsal raphe nucleus (DRN), remained unclear. We hypothesized that the hcrt projections from the LHA to LC or DRN mediate IFS-induced sleep disruption. Our results demonstrated that the IFS increased hcrt expression and the neuronal activities in the LHA, hypothalamus, brainstem, thalamus, and amygdala. Suppressions of REM sleep and slow wave activity during non-REM (NREM) sleep caused by the high expression of hcrts were blocked when a non-specific and dual hcrt receptor antagonist was administered into the LC or DRN. Furthermore, the IFS also caused an elevated innate anxiety, but was limitedly influenced by the hcrt antagonist. This result suggests that the increased hcrt concentrations in the LC and DRN mediate stress-induced sleep disruptions and might partially involve IFS-induced anxiety.

Enhanced responsiveness to hypoxic panicogenic challenge in female rats in late diestrus is suppressed by short-term, low-dose fluoxetine: Involvement of the dorsal raphe nucleus and the dorsal periaqueductal gray

Background: Acute hypoxia, which is panicogenic in humans, also evokes panic-like behavior in male rats. Panic disorder is more common in women and susceptibility increases during the premenstrual phase of the cycle. Aims: We here investigated for the first time the impact of hypoxia on the expression of panic-like escape behavior by female rats and its relationship with the estrous cycle. We also evaluated functional activation of the midbrain panic circuitry in response to this panicogenic stimulus and whether short-term, low-dose fluoxetine treatment inhibits the hyper-responsiveness of females in late diestrus. Methods: Male and female Sprague Dawley rats were exposed to 7% O2. Females in late diestrus were also tested after short-term treatment with fluoxetine (1.75 or 10 mg/kg, i.p.). Brains were harvested and processed for c-Fos and tryptophan hydroxylase immunoreactivity in the periaqueductal gray matter (PAG) and dorsal raphe nucleus (DR). Results: Acute hypoxia evoked escape in both sexes. Overall, females were more responsive than males and this is clearer in late diestrus phase. In both sexes, hypoxia induced functional activation (c-Fos expression) in non-serotonergic cells in the lateral wings of the DR and dorsomedial PAG, which was greater in late diestrus than proestrus (lowest behavioral response to hypoxia). Increased responding in late diestrus (behavioral and cellular levels) was prevented by 1.75, but not 10 mg/kg fluoxetine. Discussion: The response of female rats to acute hypoxia models panic behavior in women. Low-dose fluoxetine administered in the premenstrual phase deserves further attention for management of panic disorders in women.

Whole-brain connectivity atlas of glutamatergic and GABAergic neurons in the mouse dorsal and median raphe nuclei

The dorsal raphe nucleus (DR) and median raphe nucleus (MR) contain populations of glutamatergic and GABAergic neurons that regulate diverse behavioral functions. However, their whole-brain input-output circuits remain incompletely elucidated. We used viral tracing combined with fluorescence micro-optical sectioning tomography to generate a comprehensive whole-brain atlas of inputs and outputs of glutamatergic and GABAergic neurons in the DR and MR. We found that these neurons received inputs from similar upstream brain regions. The glutamatergic and GABAergic neurons in the same raphe nucleus had divergent projection patterns with differences in critical brain regions. Specifically, MR glutamatergic neurons projected to the lateral habenula through multiple pathways. Correlation and cluster analysis revealed that glutamatergic and GABAergic neurons in the same raphe nucleus received heterogeneous inputs and sent different collateral projections. This connectivity atlas further elucidates the anatomical architecture of the raphe nuclei, which could facilitate better understanding of their behavioral functions.

Central Nervous System Associated With Light Perception and Physiological Responses of Birds

Environmental light that animal receives (i.e., photoperiod and light intensity) has recently been shown that it affects avian central nervous system for the physiological responses to the environment by up or downregulation of dopamine and serotonin activities, and this, in turn, affects the reproductive function and stress-related behavior of birds. In this study, the author speculated on the intriguing possibility that one of the proposed avian deep-brain photoreceptors (DBPs), i.e., melanopsin (Opn4), may play roles in the dual sensory-neurosecretory cells in the hypothalamus, midbrain, and brain stem for the behavior and physiological responses of birds by light. Specifically, the author has shown that the direct light perception of premammillary nucleus dopamine-melatonin (PMM DA-Mel) neurons is associated with the reproductive activation in birds. Although further research is required to establish the functional role of Opn4 in the ventral tegmental area (VTA), dorsal raphe nucleus, and caudal raphe nucleus in the light perception and physiological responses of birds, it is an exciting prospect because the previous results in birds support this hypothesis that Opn4 in the midbrain DA and serotonin neurons may play significant roles on the light-induced welfare of birds.

Orexin receptors 1 and 2 in serotonergic neurons differentially regulate peripheral glucose metabolism in obesity

The wake-active orexin system plays a central role in the dynamic regulation of glucose homeostasis. Here we show orexin receptor type 1 and 2 are predominantly expressed in dorsal raphe nucleus-dorsal and -ventral, respectively. Serotonergic neurons in ventral median raphe nucleus and raphe pallidus selectively express orexin receptor type 1. Inactivation of orexin receptor type 1 in serotonin transporter-expressing cells of mice reduced insulin sensitivity in diet-induced obesity, mainly by decreasing glucose utilization in brown adipose tissue and skeletal muscle. Selective inactivation of orexin receptor type 2 improved glucose tolerance and insulin sensitivity in obese mice, mainly through a decrease in hepatic gluconeogenesis. Optogenetic activation of orexin neurons in lateral hypothalamus or orexinergic fibers innervating raphe pallidus impaired or improved glucose tolerance, respectively. Collectively, the present study assigns orexin signaling in serotonergic neurons critical, yet differential orexin receptor type 1- and 2-dependent functions in the regulation of systemic glucose homeostasis.