The GCN2 inhibitor IMPACT contributes to diet-induced obesity and body temperature control.

IMPACT, a highly conserved protein, is an inhibitor of the eIF2α kinase GCN2. In mammals, it is preferentially expressed in neurons. Knock-down of IMPACT expression in neuronal cells increases basal GCN2 activation and eIF2α phosphorylation and decreases translation initiation. In the mouse brain, IMPACT is particularly abundant in the hypothalamus. Here we describe that the lack of IMPACT in mice affects hypothalamic functions. Impact-/- mice (Imp-KO) are viable and have no apparent major phenotypic defect. The hypothalamus in these animals shows increased levels of eIF2α phosphorylation, as expected from the described role of IMPACT in inhibiting GCN2 and from its abundance in this brain region. When fed a normal chow, animals lacking IMPACT weight slightly less than wild-type mice. When fed a high-fat diet, Imp-KO animals gain substantially less weight due to lower food intake when compared to wild-type mice. STAT3 signaling was depressed in Imp-KO animals even though leptin levels were identical to the wild-type mice. This finding supports the observation that Imp-KO mice have defective thermoregulation upon fasting. This phenotype was partially dependent on GCN2, whereas the lean phenotype was independent of GCN2. Taken together, our results indicate that IMPACT contributes to GCN2-dependent and -independent mechanisms involved in the regulation of autonomic functions in response to energy availability.

Deep brain stimulation reverses anhedonic-like behavior in a chronic model of depression: role of serotonin and brain derived neurotrophic factor.

BACKGROUND: Deep brain stimulation (DBS) is being investigated as a treatment for major depression, but its mechanisms of action are still unknown. We have studied the effects of ventromedial prefrontal cortex (vmPFC) stimulation in a chronic model of depression and assessed the involvement of the serotonergic system and brain derived neurotrophic factor (BDNF) in a DBS response. METHODS: Rats were subjected to chronic unpredictable mild stress during 4 weeks. Decline in preference for sucrose solutions over water, an index suggested to reflect anhedonic-like behavior, was monitored on a weekly basis. The outcome of chronic vmPFC stimulation alone (8 hours/day for 2 weeks) or combined with serotonin-depleting lesions was characterized. BDNF levels were measured in the hippocampus. RESULTS: Stress induced a significant decrease in sucrose preference as well as hippocampal BDNF levels as compared with those recorded in control subjects. vmPFC stimulation completely reversed this behavioral deficit and partially increased BDNF levels. In contrast, DBS did not improve stress-induced anhedonic-like behavior in animals bearing serotonin-depleting raphe lesions with associated normal hippocampal BDNF levels. CONCLUSIONS: vmPFC stimulation was effective in a chronic model of depression. Our results suggest that the integrity of the serotonergic system is important for the anti-anhedonic-like effects of DBS but question a direct role of hippocampal BDNF.

Anterior thalamus deep brain stimulation at high current impairs memory in rats.

Deep brain stimulation (DBS) of the anterior thalamic nucleus (AN), an important relay in the circuitry of memory, is currently being proposed as a treatment for epilepsy. Despite the encouraging results with the use of this therapy, potential benefits and adverse effects are yet to be determined. We show that AN stimulation at relatively high current disrupted the acquisition of contextual fear conditioning and impaired performance on a spatial alternating task in rats. This has not been observed at parameters generating a charge density that approximated the one used in clinical practice. At settings that impaired behavior, AN stimulation induced a functional depolarization block nearby the electrode, increased c-Fos expression in cerebral regions projecting to and receiving projections from the AN, and influenced hippocampal activity. This suggests that complex mechanisms might be involved in the effects of AN DBS, including a local target inactivation and the modulation of structures at a distance. Though translating data from animals to humans has to be considered with caution, our study underscores the need for carefully monitoring memory function while selecting stimulation parameters during the clinical evaluation of AN DBS.

Microinjection of GABAergic agents into the anterior nucleus of the thalamus modulates pilocarpine-induced seizures and status epilepticus.

The anterior nucleus of the thalamus (AN) has been suggested as a potential target for seizure modulation in animal models and patients with refractory epilepsy. We investigate whether microinjections of GABAergic agonists into the AN were protective against pilocarpine-induced generalized seizures and status epilepticus (SE). Rats were treated with bilateral AN injections of muscimol (160 or 80 nmol), bicuculline (15 nmol), or saline (controls) 20 min prior to pilocarpine administration (350 mg/kg i.p.). Electrographic recordings were used to confirm seizure activity. We found that pretreatment with AN muscimol 160 nmol increased the latency to seizures and SE by 2.5-3.0-fold. This dose however was associated with side effects, particularly hypotonia. AN bicuculline was proconvulsant, whereas no major effect was observed after muscimol 80 nmol injections. The percentage of animals that developed SE was similar across groups. Overall, microinjection of high doses of muscimol into the AN delayed the occurrence of pilocarpine-induced seizures and SE but was not able to prevent these events.