Acute THPVP inactivation decreases the glucagon and sympathoadrenal responses to recurrent hypoglycemia

Al-Noori, Salwa; Sanders, Nicole M.; Taborsky, Gerald J.; Wilkinson, Charles W.; Figlewicz, Dianne P.

doi:10.1016/j.brainres.2007.11.040

Cited by 5 publications

(5 citation statements)

References 33 publications

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“…9). This is consistent with its importance in modulating the CRR to hypoglycemia, as we and others have recently documented (1,4). Whereas studies in models of seizure and Parkinson's disease (2,13,44) implicate a role for FosB expression in the amygdala and striatum, our finding represents the first report, to our knowledge, of expression of FosB isoforms in the PVN and in response to a metabolic stressor.…”

Section: Discussionsupporting

confidence: 92%

Recurrent hypoglycemia alters hypothalamic expression of the regulatory proteins FosB and synaptophysin

Al-Noori

Sanders

Taborsky

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

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A limiting factor to the clinical management of diabetes is iatrogenic hypoglycemia. With multiple hypoglycemic episodes, the collective neuroendocrine response that restores euglycemia is impaired. In our animal model of recurrent hypoglycemia (RH), neuroendocrine deficits are accompanied by a decrease in medial hypothalamic activation. Here we tested the hypothesis that the medial hypothalamus may exhibit unique changes in the expression of regulatory proteins in response to RH. We report that expression of the immediate early gene FosB is increased in medial hypothalamic nuclei, anterior hypothalamus, and posterior paraventricular nucleus of the thalamus (THPVN) of the thalamus following RH. We identified the hypothalamic PVN, a key autonomic output site, among the regions expressing FosB. To identify the subtype(s) of neuronal populations that express FosB, we screened candidate neuropeptides of the PVN for coexpression using dual fluorescence immunohistochemistry. Among the neuropeptides analyzed [including oxytocin, vasopressin, thyrotropin-releasing hormone, and corticotropin-releasing factor (CRF)], FosB was only identified in CRF-positive neurons. Inhibitory gamma-aminobutyric acid-positive processes appear to impinge on these FosB-expressing neurons. Finally, we observed a significant decrease in the presynaptic marker synaptophysin within the PVN of RH-treated vs. saline-treated rats, suggesting that rapid alterations of synaptic morphology may occur in association with RH. Collectively, these data suggest that RH stress triggers cellular changes that support synaptic plasticity, in specific neuroanatomical sites, which may contribute to the development of hypoglycemia-associated autonomic failure.

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Section: Discussionsupporting

confidence: 92%

Recurrent hypoglycemia alters hypothalamic expression of the regulatory proteins FosB and synaptophysin

Al-Noori

Sanders

Taborsky

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

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“…It may be the case that the transient decreases in blood glucose achieved by our insulin regimen induced adaptations in neuronal glucose metabolism (Jiang et al, 2009) that may have counteracted oxidative stress in the juvenile brain. However, these and other adaptations, including enhanced excitability in the amygdala (in juveniles) (Lee et al, 1988), increased activity in midline thalamic nuclei (Al-Noori et al, 2008a; Arbelaez et al, 2008), and alterations in multiple hypothalamic subnuclei (Chan et al, 2008; Evans et al, 2001), may also contribute to altered function of circuits that regulate fear-related behaviors and stress responses. Importantly, these changes in neuronal function may not be accompanied by standard histological markers of neuropathology.…”

Section: Discussionmentioning

confidence: 99%

Moderate recurrent hypoglycemia during early development leads to persistent changes in affective behavior in the rat

Moore

Craft

Grimaldi

et al. 2010

Brain, Behavior, and Immunity

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Recurrent hypoglycemia is a common problem among infants and children that is associated with several metabolic disorders and insulin-dependent diabetes mellitus. Although studies have reported a relationship between a history of juvenile hypoglycemia and psychological health problems, the direct effects of recurrent moderate hypoglycemia have not been fully determined. Thus, in this study, we used an animal model to examine the effects of recurrent hypoglycemia during the juvenile period on affective, social, and motor function (assessed under euglycemic conditions) across development. To model recurrent hypoglycemia, rats were administered 5 U/kg of insulin or saline twice per day from postnatal day (P)10 to P19. Body weight gain was retarded in insulin-treated rats during the treatment period, but recovered by the end of treatment. However, insulin-treated rats displayed increases in affective reactivity that emerged early during treatment and persisted after treatment into early adulthood. Specifically, insulin-treated pups showed increased maternal separation-induced vocalizations as infants, and an exaggerated acoustic startle reflex as juveniles and young adults. Moreover, young adult rats with a history of recurrent juvenile hypoglycemia exhibited increased fear-potentiated startle and increases in behavioral and hormonal responses to restraint stress. Some of these effects were sex-dependent. The changes in affective behavior in insulin-exposed pups were accompanied by decreases in adolescent social play behavior. These results provide evidence that recurrent, transient hypoglycemia during juvenile development can lead to increases in fear-related behavior and stress reactivity. Importantly, these phenotypes are not reversed with normalization of blood glucose and may persist into adulthood.

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“…While the thalamus is primarily known to be involved in the processing and relaying of sensory information, regulation of sleep, awareness, and motor activity, there is growing evidence that it may play a role in glucose sensing. For instance, there are several reports that the posterior paraventricular nucleus of the thalamus (THPVP) has been shown to respond to hypoglycemia (Teves et al, 2004; Al-Noori et al, 2008). …”

Section: Discussionmentioning

confidence: 99%

Expression of the diabetes‐associated gene TCF7L2 in adult mouse brain

Lee

Elias

et al. 2009

J of Comparative Neurology

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Polymorphisms of the gene TCF7L2 (transcription factor 7-like 2) are strongly associated with the development and progression of type 2 diabetes. TCF7L2 is important in the development of peripheral organs such as adipocytes, pancreas, and the intestine. However, very little is known about its expression elsewhere. In this study we used in situ hybridization histochemistry to show that TCF7L2 has a unique expression pattern in the mouse brain. TCF7L2 is expressed in two distinct populations. First, it is highly ex pressed in thalamic and tectal structures. Additionally, TCF7L2 mRNA is expressed at moderate to low levels in specific cells of the hypothalamus, preoptic nucleus, and circumventricular organs. Collectively, these patterns of expression suggest that TCF7L2 has distinct functions within the brain, with a general role in the development and maintenance of thalamic and midbrain neurons, and then a distinct role in autonomic homeostasis.

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Acute THPVP inactivation decreases the glucagon and sympathoadrenal responses to recurrent hypoglycemia

Cited by 5 publications

References 33 publications

Recurrent hypoglycemia alters hypothalamic expression of the regulatory proteins FosB and synaptophysin

Recurrent hypoglycemia alters hypothalamic expression of the regulatory proteins FosB and synaptophysin

Moderate recurrent hypoglycemia during early development leads to persistent changes in affective behavior in the rat

Expression of the diabetes‐associated gene TCF7L2 in adult mouse brain

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