Distribution of vesicular glutamate transporter mRNA in rat hypothalamus

Ziegler, Dana R.; Cullinan, William E.; Herman, James P.

doi:10.1002/cne.10257

Cited by 233 publications

(239 citation statements)

References 44 publications

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“…The Vgat-ires-Cre triggered reexpression of RIIβ in the DMH, ARC, and LH, but not the VMH and PVH regions of the hypothalamus (Fig. 6A), as expected, because these latter areas are primarily composed of glutamatergic neurons (23,24). Reexpression of RIIβ is also strong in the striatum (Fig.…”

Section: Specific Riiβ Reexpression In Striatum Reverses the Hyperactsupporting

confidence: 75%

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Deficiency of the RIIβ subunit of PKA affects locomotor activity and energy homeostasis in distinct neuronal populations

Zheng¹,

Yang²,

Sikorski³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Targeted disruption of RIIβ-protein kinase A (PKA) in mice leads to a lean phenotype, increased nocturnal locomotor activity, and activation of brown adipose tissue. Because RIIβ is abundantly expressed in both white and brown adipose tissue as well as the brain, the contribution of neuronal vs. peripheral PKA to these phenotypes was investigated. We used a Cre-Lox strategy to reexpress RIIβ in a tissue-specific manner in either adipocytes or neurons. Mice with adipocyte-specific RIIβ reexpression remained hyperactive and lean, but pan-neuronal RIIβ reexpression reversed both phenotypes. Selective RIIβ reexpression in all striatal medium spiny neurons with Darpp32-Cre corrected the hyperlocomotor phenotype, but the mice remained lean. Further analysis revealed that RIIβ reexpression in D2 dopamine receptor-expressing medium spiny neurons corrected the hyperlocomotor phenotype, which demonstrated that the lean phenotype in RIIβ-PKA-deficient mice does not develop because of increased locomotor activity. To identify the neurons responsible for the lean phenotype, we used specific Cre-driver mice to reexpress RIIβ in agouti-related peptide (AgRP)-, proopiomelanocortin (POMC)-, single-minded 1 (Sim1)-, or steroidogenic factor 1 (SF1)-expressing neurons in the hypothalamus, but observed no rescue of the lean phenotype. However, when RIIβ was reexpressed in multiple regions of the hypothalamus and striatum driven by Rip2-Cre, or specifically in GABAergic neurons driven by Vgat-ires-Cre, both the hyperactive and lean phenotypes were completely corrected. Bilateral injection of adeno-associated virus1 (AAV1)-Cre directly into the hypothalamus caused reexpression of RIIβ and partially reversed the lean phenotype. These data demonstrate that RIIβ-PKA deficiency in a subset of hypothalamic GABAergic neurons leads to the lean phenotype.mouse genetics | obesity | exercise | cAMP W e reported previously that mice lacking the protein kinase A (PKA) regulatory subunit RΙΙβ (RΙΙβ KO) exhibit a 50% reduction in white adipose tissue (WAT) and are resistant to dietinduced obesity (DIO) and diabetes (1, 2). These mice have an extended lifespan and show diminished age-related metabolic dysfunctions such as fatty liver and insulin resistance (3). Compared with their WT littermates, RIIβ KO mice have normal to slightly increased food intake, a twofold increase in nocturnal physical activity, and a basal metabolic rate (VO 2 consumption) that is higher than WT if calculated based on total body weight (4-6). RIIβ is highly expressed in the mouse CNS, brown adipose tissue (BAT), and WAT with limited expression elsewhere (1, 7-9). At the molecular level, RIIβ deficiency is accompanied by a compensatory increase in the PKA regulatory subunit RIα, which results in increased basal PKA activity and decreased total C subunit activity in brain, BAT, and WAT (1). These changes in PKA subunit composition may also alter PKA holoenzyme localization to specific signaling complexes because RIIβ has a much higher affinity for anchoring proteins (AKAPs)...

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Section: Specific Riiβ Reexpression In Striatum Reverses the Hyperactsupporting

confidence: 75%

“…8. Vgat-ires-Cre activates RIIβ expression in multiple nuclei of the hypothalamus with the notable exception of the PVN and VMH, where glutamatergic neurons predominate (23,24). In the arcuate nucleus, Vgat-ires-Cre was shown to be expressed in neurons, including AgRP neurons but not POMC neurons (23).…”

Section: Discussionmentioning

confidence: 97%

Deficiency of the RIIβ subunit of PKA affects locomotor activity and energy homeostasis in distinct neuronal populations

Zheng¹,

Yang²,

Sikorski³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Recent work has focused on the role of intracellular glucose sensors, neurotransmitters such as gamma-aminobutyric acid (GABA), glutamate, serotonin, and neuropeptides [corticotrophin-releasing hormone (CRH) and urocortins] (1, 30). Most VMN SF1 neurons are glutamatergic (39,40), and previous evidence points to a role for glutamate release from these neurons in the CRR response (11). However, our data suggest that not all VMN SF1 neurons participate in glucose counterregulation because photoactivation of VMN LepRb neurons, many of which express SF1 and are also glutamatergic (21,22), was without effect on either glycemia or secretion of counterregulatory hormones.…”

Section: Discussioncontrasting

confidence: 49%

Functional identification of a neurocircuit regulating blood glucose

Meek

Nelson

Matsen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

159

187

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Previous studies implicate the hypothalamic ventromedial nucleus (VMN) in glycemic control. Here, we report that selective inhibition of the subset of VMN neurons that express the transcription factor steroidogenic-factor 1 (VMN SF1 neurons) blocks recovery from insulin-induced hypoglycemia whereas, conversely, activation of VMN SF1 neurons causes diabetes-range hyperglycemia. Moreover, this hyperglycemic response is reproduced by selective activation of VMN SF1 fibers projecting to the anterior bed nucleus of the stria terminalis (aBNST), but not to other brain areas innervated by VMN SF1 neurons. We also report that neurons in the lateral parabrachial nucleus (LPBN), a brain area that is also implicated in the response to hypoglycemia, make synaptic connections with the specific subset of glucoregulatory VMN SF1 neurons that project to the aBNST. These results collectively establish a physiological role in glucose homeostasis for VMN SF1 neurons and suggest that these neurons are part of an ascending glucoregulatory LPBN→VMN SF1 →aBNST neurocircuit.glucoregulatory circuit | counter regulation | ventromedial nucleus | bed nucleus of the stria terminalis | hyperglycemia B ecause the brain relies exclusively on glucose as a fuel source, brain function is rapidly compromised when circulating glucose levels drop below the normal range. Consequently, hypoglycemia elicits a robust, integrated, and redundant set of counterregulatory responses (CRRs) that ensure the rapid and efficient recovery of plasma glucose concentrations into the normal range (1). Components of the CRR include increased secretion of the hormones glucagon, epinephrine, and glucocorticoids, inhibition of glucoseinduced insulin secretion, increased sympathetic nervous system (SNS) outflow to the liver, and increased food intake (1-3). Owing to this redundancy, recovery from hypoglycemia is difficult to block in normal humans and animal models, even when adrenal or glucagon responses are prevented. Only when multiple responses are blocked is the ability to recover from hypoglycemia significantly compromised (4). This arrangement is perhaps unsurprising, given the threat to survival posed by hypoglycemia.Although glucose sensing can occur at peripheral (e.g., neurons innervating the hepatic portal vein) as well as central sites (3, 5), the brain is the organ responsible both for transducing this information into effective glucose counterregulation and for terminating this response once euglycemia is restored. Of the many brain areas that have been investigated, the hypothalamic ventromedial nucleus (VMN) has emerged as potentially being both necessary and sufficient to elicit this powerful response. This assertion is based on evidence that, whereas electrical stimulation of the VMN activates the CRR and thereby raises circulating glucose levels (6), glucose infusion directly into the VMN can suppress the CRR during hypoglycemia (7) and thereby impair recovery of normal blood glucose levels (8). Moreover, two recent papers identified a circuit comprise...

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“…Although the phenotype of these neurons is unknown, there are several types of candidate neurons present in this region of the hypothalamus. For example, glutamatergic neurons that are present in this area regulate the excitability of hypocretinergic and other local neurons , Ziegler, et al, 2002, and nitrergic neurons of the postero-lateral hypothalamus of the guinea pig project to the hypoglossal and trigeminal motor nuclei (McGregor, et al, 2004, McGregor, et al, 2005. In this regard, we have observed nitrergic cells intermingled with MCHergic and hypocretinergic somata in this region of the cat (unpublished).…”

Section: Discussionmentioning

confidence: 63%

MCH-containing neurons in the hypothalamus of the cat: Searching for a role in the control of sleep and wakefulness

Torterolo

Sampogna²,

Morales

et al. 2006

Brain Research

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Neurons that utilize melanin-concentrating hormone (MCH) and others that employ hypocretin as neurotransmitter are located in the hypothalamus and project diffusely throughout the CNS, including areas that participate in the generation and maintenance of the states of sleep and wakefulness. In the present report, immunohistochemical methods were employed to examine the distribution of MCHergic and hypocretinergic neurons. In order to test the hypothesis that the MCHergic system is capable of influencing specific behavioral states, we studied Fos immunoreactivity in MCHcontaining neurons during 1) quiet wakefulness, 2) active wakefulness with motor activity, 3) active wakefulness without motor activity, 4) quiet sleep, and, 5) active sleep induced by carbachol (AScarbachol). We determined that MCHergic neuronal somata in the cat are intermingled with hypocretinergic neurons in the dorsal and lateral hypothalamus, principally in the tuberal and tuberomammillary regions; however, hypocretinergic neurons extended more in the anteriorposterior axis than MCHergic neurons. Axosomatic and axodendritic contacts were common between these neurons. In contrast to hypocretinergic neurons, which are known to be active during motor activity and AS-carbachol, Fos immunoreactivity was not observed in MCH-containing neurons in conjunction with any of the preceding behavioral conditions. Non-MCHergic, non-hypocretinergic neurons that expressed c-fos during active wakefulness with motor activity were intermingled with MCH and hypocretin-containing neurons, suggesting that these neurons are related to some aspect of motor function. Further studies are required to elucidate the functional sequela of the interactions between MCHergic and hypocretinergic neurons and the phenotype of the other neurons that were active during motor activity.

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Distribution of vesicular glutamate transporter mRNA in rat hypothalamus

Cited by 233 publications

References 44 publications

Deficiency of the RIIβ subunit of PKA affects locomotor activity and energy homeostasis in distinct neuronal populations

Deficiency of the RIIβ subunit of PKA affects locomotor activity and energy homeostasis in distinct neuronal populations

Functional identification of a neurocircuit regulating blood glucose

MCH-containing neurons in the hypothalamus of the cat: Searching for a role in the control of sleep and wakefulness

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