The lateral parabrachial nucleus (LPBN) is known to relay noxious information to the amygdala for processing affective responses. However, it is unclear whether the LPBN actively processes neuropathic pain characterized by persistent hyperalgesia with aversive emotional responses. Here we report that neuropathic pain-like hypersensitivity induced by common peroneal nerve (CPN) ligation increases nociceptive stimulation-induced responses in glutamatergic LPBN neurons. Optogenetic activation of GABAergic LPBN neurons does not affect basal nociception, but alleviates neuropathic pain-like behavior. Optogenetic activation of glutamatergic or inhibition of GABAergic LPBN neurons induces neuropathic pain-like behavior in naïve mice. Inhibition of glutamatergic LPBN neurons alleviates both basal nociception and neuropathic pain-like hypersensitivity. Repetitive pharmacogenetic activation of glutamatergic or GABAergic LPBN neurons respectively mimics or prevents the development of CPN ligation-induced neuropathic pain-like hypersensitivity. These findings indicate that a delicate balance between excitatory and inhibitory LPBN neuronal activity governs the development and maintenance of neuropathic pain.

Amyloid β (Aβ) oligomer-induced aberrant neurotransmitter release is proposed to be a crucial early event leading to synapse dysfunction in Alzheimer’s disease (AD). In the present study, we report that the release probability (Pr) at the synapse between the Schaffer collateral (SC) and CA1 pyramidal neurons is significantly reduced at an early stage in mouse models of AD with elevated Aβ production. High nanomolar synthetic oligomeric Aβ42 also suppresses Pr at the SC-CA1 synapse in wild-type mice. This Aβ-induced suppression of Pr is mainly due to an mGluR5-mediated depletion of phosphatidylinositol-4,5-bisphosphate (PIP2) in axons. Selectively inhibiting Aβ-induced PIP2 hydrolysis in the CA3 region of the hippocampus strongly prevents oligomeric Aβ-induced suppression of Pr at the SC-CA1 synapse and rescues synaptic and spatial learning and memory deficits in APP/PS1 mice. These results first reveal the presynaptic mGluR5-PIP2 pathway whereby oligomeric Aβ induces early synaptic deficits in AD.

Foraging food in a novel environment is essential for survival. Animals coordinate the complex motivated states and decide whether to initiate feeding or escape from unfamiliar scenes. Neurons in the paraventricular thalamic nucleus (PVT) receive multiple inputs from the hypothalamus, forebrain, and caudal brainstem that are known to regulate feeding behavior. The PVT neurons also project to the forebrain regions that are involved in reward and motivation. Notably, the PVT neurons projecting to the nucleus accumbens (NAc) are activated when an incentive stimulus is presented. Optogenetic activation of the PVT-NAc path has been shown to increase the motivation for sucrose-seeking in instrumental tasks. However, how the PVT circuitry regulates the feeding behavior in a novel environment remains largely obscure. In the present study, we found that the activity of glutamatergic neurons in the anterior PVT (aPVT) projecting to the NAc dictates the novelty-suppressed feeding behavior in mice. Optogenetic activation of the aPVT-NAc projection increased the feeding time and food consumption in mice under a moderate food restriction in a novel open field where the food was placed in the central area. The exploratory and anxiety-like behaviors, however, were not altered by the aPVT-NAc activation. Our work reveals that activation of the aPVT-NAc pathway in mice generates a motivation to consume food in a novel environment.

No abstract

No abstract