GABAergic basal forebrain projections to the periaqueductal gray promote food consumption, reward and predation

Behaviors central to the procurement and consumption of food are among those most fundamental to survival, but their inappropriate expression can lead to overeating and obesity. Nevertheless, we have a poor understanding of circuits that promote feeding independent of physiological demand. Here we demonstrate that activation of basal forebrain (BF) GABAergic neurons results in consumption of food as well as non-food items in well-fed mice, and performance of fictive eating in the absence of ingestible materials. In addition, stimulation of these cells disrupts defensive threat responses and elicits reward-like motivational effects. Finally, BF GABAergic activity triggers skilled predatory attacks of live prey and prey-like objects, but not social targets. These effects were entirely recapitulated by selective stimulation of BF GABAergic projections to the periaqueductal gray (PAG). Our results outline a potent circuit mechanism for increased feeding through recruitment of distinct but synergistic behaviors, and add to growing evidence that PAG is an important integrator of feeding-related activity.

The effect of zolpidem on targeted memory reactivation during sleep

According to the active system consolidation theory, memory consolidation during sleep relies on the reactivation of newly encoded memory representations. This reactivation is orchestrated by the interplay of sleep slow oscillations, spindles, and theta, which are in turn modulated by certain neurotransmitters like GABA to enable long-lasting plastic changes in the memory store. Here we asked whether the GABAergic system and associated changes in sleep oscillations are functionally related to memory reactivation during sleep. We administered the GABAA agonist zolpidem (10 mg) in a double-blind placebo-controlled study. To specifically focus on the effects on memory reactivation during sleep, we experimentally induced such reactivations by targeted memory reactivation (TMR) with learning-associated reminder cues presented during post-learning slow-wave sleep (SWS). Zolpidem significantly enhanced memory performance with TMR during sleep compared with placebo. Zolpidem also increased the coupling of fast spindles and theta to slow oscillations, although overall the power of slow spindles and theta was reduced compared with placebo. In an uncorrected exploratory analysis, memory performance was associated with slow spindle responses to TMR in the zolpidem condition, whereas it was associated with fast spindle responses in placebo. These findings provide tentative first evidence that GABAergic activity may be functionally implicated in memory reactivation processes during sleep, possibly via its effects on slow oscillations, spindles and theta as well as their interplay.

Identification of Dihydromyricetin and Metabolites in Serum and Brain Associated with Acute Anti-Ethanol Intoxicating Effects in Mice

Dihydromyricetin is a natural bioactive flavonoid with unique GABAA receptor activity with a putative mechanism of action to reduce the intoxication effects of ethanol. Although dihydromyricetin’s poor oral bioavailability limits clinical utility, the promise of this mechanism for the treatment of alcohol use disorder warrants further investigation into its specificity and druggable potential. These experiments investigated the bioavailability of dihydromyricetin in the brain and serum associated with acute anti-intoxicating effects in C57BL/6J mice. Dihydromyricetin (50 mg/kg IP) administered 0 or 15-min prior to ethanol (PO 5 g/kg) significantly reduced ethanol-induced loss of righting reflex. Total serum exposures (AUC0→24) of dihydromyricetin (PO 50 mg/kg) via oral (PO) administration were determined to be 2.5 µM × h (male) and 0.7 µM × h (female), while intraperitoneal (IP) administration led to 23.8-fold and 7.2- increases in AUC0→24 in male and female mice, respectively. Electrophysiology studies in α5β3γ2 GABAA receptors expressed in Xenopus oocytes suggest dihydromyricetin (10 µM) potentiates GABAergic activity (+43.2%), and the metabolite 4-O-methyl-dihydromyricetin (10 µM) negatively modulates GABAergic activity (−12.6%). Our results indicate that administration route and sex significantly impact DHM bioavailability in mice, which is limited by poor absorption and rapid clearance. This correlates with the observed short duration of DHM’s anti-intoxicating properties and highlights the need for further investigation into mechanism of DHM’s potential anti-intoxicating properties.

Altered Spontaneous Glutamatergic and GABAergic Activity in the Peritumoral Cortex of Low-Grade Gliomas Presenting With History of Seizures

The peritumoral regions of WHO grade II gliomas, like astrocytoma and oligodendroglioma, have been reported to show epileptiform activities. An imbalance of glutamatergic and GABAergic mechanisms is primarily responsible for the generation of epileptiform activities. Here we have compared the electrophysiological properties of pyramidal neurons in intraoperative peritumoral specimens obtained from glioma patients with (GS) and without (GN) a history of seizures at presentation. Histology and immunohistochemistry were performed to assess the infiltration of proliferating cells at the peritumoral tissues. Whole-cell patch clamp technique was performed to measure the spontaneous glutamatergic and GABAergic activity onto pyramidal neurons in the peritumoral samples of GS (n = 11) and GN (n = 15) patients. The cytoarchitecture of the peritumoral tissues was devoid of Ki67 immuno-positive cells. We observed a higher frequency of spontaneous glutamatergic and GABAergic activities onto pyramidal neurons of the peritumoral samples of GS patients. Our findings suggest that, in spite of similar histopathological features, the pyramidal neurons in the peritumoral samples of GS and GN patients showed differences in spontaneous excitatory and inhibitory synaptic neurotransmission. An alteration in postsynaptic currents may contribute to the spontaneous epileptiform activity in GS patients.

GABAergic basal forebrain projections to the periaqueductal gray promote food consumption, reward and predation

Behaviors central to the procurement and consumption of food are among those most fundamental to survival, but their inappropriate expression can lead to overeating and obesity. Nevertheless, we have a poor understanding of circuits that promote feeding independent of physiological demand. Here we demonstrate that activation of basal forebrain (BF) GABAergic neurons results in consumption of food as well as non-food items in well-fed mice, and performance of fictive eating in the absence of ingestible materials. In addition, stimulation of these cells disrupts defensive threat responses and elicits reward-like motivational effects. Finally, BF GABAergic activity triggers skilled predatory attack of live prey and prey-like objects, but not social targets. These effects were entirely recapitulated by selective stimulation of BF GABAergic projections to the periacqueductual gray (PAG). Our results outline a potent circuit mechanism for increased feeding through recruitment of distinct but synergistic behaviors, and add to growing evidence that PAG is an important integrator of feeding-related activity.

Ventral tegmental area GABA neurons mediate stress-induced blunted reward-seeking in mice

Decreased pleasure-seeking (anhedonia) forms a core symptom of depression. Stressful experiences precipitate depression and disrupt reward-seeking, but it remains unclear how stress causes anhedonia. We recorded simultaneous neural activity across limbic brain areas as mice underwent stress and discovered a stress-induced 4 Hz oscillation in the nucleus accumbens (NAc) that predicts the degree of subsequent blunted reward-seeking. Surprisingly, while previous studies on blunted reward-seeking focused on dopamine (DA) transmission from the ventral tegmental area (VTA) to the NAc, we found that VTA GABA, but not DA, neurons mediate stress-induced blunted reward-seeking. Inhibiting VTA GABA neurons disrupts stress-induced NAc oscillations and rescues reward-seeking. By contrast, mimicking this signature of stress by stimulating NAc-projecting VTA GABA neurons at 4 Hz reproduces both oscillations and blunted reward-seeking. Finally, we find that stress disrupts VTA GABA, but not DA, neural encoding of reward anticipation. Thus, stress elicits VTA-NAc GABAergic activity that induces VTA GABA mediated blunted reward-seeking.

Neuregulin 1/ErbB4 signaling contributes to the anti-epileptic effects of the ketogenic diet

Background The ketogenic diet (KD) has been recognized as a potentially effective therapy to treat neuropsychiatric diseases, including epilepsy. Previous studies have indicated that KD treatment elevates γ-Amino butyric acid (GABA) levels in both human and murine brains, which presumably contributes to the KD’s anti-seizure effects. However, this has not been systematically investigated at the synaptic level, and the underlying molecular mechanisms remain to be elucidated. Methods Kainic acid (KA)-induced acute and chronic seizure models were utilized to examine the effects of KD treatment on seizure threshold and epileptogenesis. Synaptic activities in the hippocampus were recorded with the technique of electrophysiology. The effects of the KD on Neuregulin 1 (Nrg1) expression were assessed via RNA sequencing, real-time PCR and Western blotting. The obligatory role of Nrg1 in KD’s effects on seizures was evaluated through disruption of Nrg1 signaling in mice by genetically deleting its receptor-ErbB4. Results We found that KD treatment suppressed seizures in both acute and chronic seizure models and enhanced presynaptic GABA release probability in the hippocampus. By screening molecular targets linked to GABAergic activity with transcriptome analysis, we identified that KD treatment dramatically increased the Nrg1 gene expression in the hippocampus. Disruption of Nrg1 signaling by genetically deleting its receptor-ErbB4 abolished KD’s effects on GABAergic activity and seizures. Conclusion Our findings suggest a critical role of Nrg1/ErbB4 signaling in mediating KD’s effects on GABAergic activity and seizures, shedding light on developing new therapeutic interventions to seizure control.

A randomized phase 1 single-dose polysomnography study of ASP8062, a GABAB receptor positive allosteric modulator

Rationale Previous research suggests that sleep polysomnography and EEG endpoints can be used to assess GABAergic activity; however, the impact of GABAB receptor positive allosteric modulators on sleep endpoints remains unclear. Objectives This phase 1 study compared a single dose of ASP8062 (35 mg or 70 mg), a GABAB receptor positive allosteric modulator, with placebo and paroxetine (40 mg). Methods Healthy adult volunteers were randomized to four treatments (35 mg ASP8062, 70 mg ASP8062, paroxetine 40 mg, or matching placebo), each separated by a 14-day washout. Primary endpoints obtained by polysomnography were time in stage N3 or SWS and time in rapid eye movement (REM) sleep. Secondary endpoints included impact on sleep stages and electroencephalography parameters, pharmacokinetics, nighttime growth hormone (GH), and safety/tolerability. Results In 20 randomized volunteers, ASP8062 led to a significant and seemingly dose-dependent increase in SWS over the entire night; this increase was mainly observed during the first third of the night. ASP8062 did not impact time in REM sleep. Paroxetine had no effect on SWS but produced a significant reduction in time spent in REM sleep. A dose-dependent trend in increased GH release was also observed with ASP8062. Headache and nausea were the most commonly reported treatment-emergent adverse events (TEAEs) for ASP8062; most TEAEs were mild in severity. Conclusions Single-dose ASP8062 (35 and 70 mg) appeared to result in CNS penetration and enhanced GABAergic activity as measured by increases in slow-wave sleep and growth hormone release.

Partial reinforcement in rat autoshaping with a long CS: Effects of pramipexole and chlordiazepoxide on sign and goal tracking

In Pavlovian autoshaping, sign-tracking responses (lever pressing) to a conditioned stimulus (CS) are usually invigorated under partial reinforcement (PR) compared to continuous reinforcement (CR). This effect, called the PR acquisition effect (PRAE), can be interpreted in terms of increased incentive hope or frustration-induced drive derived from PR training. Incentive hope and frustration have been related to dopaminergic and GABAergic activity, respectively. We examined the within-trial dynamics of sign and goal tracking in rats exposed to 20-s-long lever presentations during autoshaping acquisition under PR vs. CR conditions under the effects of drugs tapping on dopamine and GABA activity. There was no evidence of the PRAE in these results, both groups showing high, stable sign-tracking response rates. However, the pharmacological treatments affected behavior as revealed in within-trial changes. The dopamine D2 receptor agonist pramipexole (0.4 mg/kg) suppressed lever pressing and magazine entries relative to saline controls in a within-subject design, but only in PR animals. The allosteric benzodiazepine chlordiazepoxide (5 mg/kg) failed to affect either sign or goal tracking in either CR or PR animals. These results emphasize the roles of dopamine and GABA receptors in autoshaping performance, but remain inconclusive with respect to incentive hope and frustration theories. Some aspects of within-trial changes in sign and goal tracking are consistent with a mixture of reward timing and response competition.