A thalamic nucleus reuniens-lateral septum-lateral hypothalamus circuit for comorbid anxiety-like behaviors in chronic itch.

Chronic itch often clinically coexists with anxiety symptoms, creating a vicious cycle of itch-anxiety comorbidities that are difficult to treat. However, the neuronal circuit mechanisms underlying the comorbidity of anxiety in chronic itch remain elusive. Here, we report anxiety-like behaviors in mouse models of chronic itch and identify γ-aminobutyric acid-releasing (GABAergic) neurons in the lateral septum (LS) as the key player in chronic itch-induced anxiety. In addition, chronic itch is accompanied with enhanced activity and synaptic plasticity of excitatory projections from the thalamic nucleus reuniens (Re) onto LS GABAergic neurons. Selective chemogenetic inhibition of the Re → LS circuit notably alleviated chronic itch-induced anxiety, with no impact on anxiety induced by restraint stress. Last, GABAergic neurons in lateral hypothalamus (LH) receive monosynaptic inhibition from LS GABAergic neurons to mediate chronic itch-induced anxiety. These findings underscore the potential significance of the Re → LS → LH pathway in regulating anxiety-like comorbid symptoms associated with chronic itch.

Institutional Residence Protects Against Cognitive Frailty: A Cross-Sectional Study.

Based on the complex aging background, more and more older people have to live in an institution in later life in China. The prevalence of cognitive frailty (CF) is more higher in institutions than in communities. Rarely studies were conducted on the relationship between institutional residence and CF. Hence, this study were performed to determine the relationship between institutional residence (living in a nursing home) and CF in older adults. A total of 1004 older community residents and 111 older nursing home residents over 50 years of age from Hefei, Anhui Province, China were recruited. CF included physical frailty (PF) and mild cognitive impairment (MCI). PF was assessed using the Chinese version of the Fried frailty scale, MCI was assessed using the Montreal Cognitive Assessment, and the common associated factors including sedentary behavior, exercise, intellectual activity, comorbidity, medication, chronic pain, sleep disorders, nutritional status and loneliness were analyzed using regression logistic models. Multivariate regression logistic analysis showed that exercise (P = .019, odds ratio [OR] = 0.494, 95% confidence interval [CI]: 0.274-0.891), intellectual activity (P = .019, OR = 0.595, 95% CI: 0.380-0.932), medication use (P = .003, OR = 2.388, 95% CI: 1.339-4.258), chronic pain (P = .003, OR = 1.580, 95% CI: 1.013-2.465) and loneliness (P = .000, OR = 2.991, 95% CI: 1.728-5.175) were significantly associated with CF in community residents; however, only sedentary behavior (P = .013, OR = 3.851, 95% CI: 1.328-11.170) was significantly associated with CF in nursing home residents. Our findings suggest that nursing homes can effectively address many common risk factors for CF, including lack of exercise and intellectual activity, medication use, chronic pain, and loneliness, better than the community setting. Thus, residing in a nursing home is conducive to the intervention of CF.

Representation and control of pain and itch by distinct prefrontal neural ensembles.

Pain and itch are two closely related but essentially distinct sensations that elicit different behavioral responses. However, it remains mysterious how pain and itch information is encoded in the brain to produce differential perceptions. Here, we report that nociceptive and pruriceptive signals are separately represented and processed by distinct neural ensembles in the prelimbic (PL) subdivision of the medial prefrontal cortex (mPFC) in mice. Pain- and itch-responsive cortical neural ensembles were found to significantly differ in electrophysiological properties, input-output connectivity profiles, and activity patterns to nociceptive or pruriceptive stimuli. Moreover, these two groups of cortical neural ensembles oppositely modulate pain- or itch-related sensory and emotional behaviors through their preferential projections to specific downstream regions such as the mediodorsal thalamus (MD) and basolateral amygdala (BLA). These findings uncover separate representations of pain and itch by distinct prefrontal neural ensembles and provide a new framework for understanding somatosensory information processing in the brain.

Protein Kinase C Lambda Mediates Acid-Sensing Ion Channel 1a-Dependent Cortical Synaptic Plasticity and Pain Hypersensitivity.

Chronic pain is a serious debilitating disease for which effective treatment is still lacking. Acid-sensing ion channel 1a (ASIC1a) has been implicated in nociceptive processing at both peripheral and spinal neurons. However, whether ASIC1a also contributes to pain perception at the supraspinal level remains elusive. Here, we report that ASIC1a in ACC is required for thermal and mechanical hypersensitivity associated with chronic pain. ACC-specific genetic deletion or pharmacological blockade of ASIC1a reduced the probability of cortical LTP induction and attenuated inflammatory thermal hyperalgesia and mechanical allodynia in male mice. Using cell type-specific manipulations, we demonstrate that ASIC1a in excitatory neurons of ACC is a major player in cortical LTP and pain behavior. Mechanistically, we show that ASIC1a tuned pain-related cortical plasticity through protein kinase C λ-mediated increase of membrane trafficking of AMPAR subunit GluA1 in ACC. Importantly, postapplication of ASIC1a inhibitors in ACC reversed previously established nociceptive hypersensitivity in both chronic inflammatory pain and neuropathic pain models. These results suggest that ASIC1a critically contributes to a higher level of pain processing through synaptic potentiation in ACC, which may serve as a promising analgesic target for treatment of chronic pain.SIGNIFICANCE STATEMENT Chronic pain is a debilitating disease that still lacks effective therapy. Ion channels are good candidates for developing new analgesics. Here, we provide several lines of evidence to support an important role of cortically located ASIC1a channel in pain hypersensitivity through promoting long-term synaptic potentiation in the ACC. Our results indicate a promising translational potential of targeting ASIC1a to treat chronic pain.

Central Processing of Itch in the Midbrain Reward Center.

Itch is an aversive sensation that evokes a desire to scratch. Paradoxically, scratching the itch also produces a hedonic experience. The specific brain circuits processing these different aspects of itch, however, remain elusive. Here, we report that GABAergic (GABA) and dopaminergic (DA) neurons in the ventral tegmental area (VTA) are activated with different temporal patterns during acute and chronic itch. DA neuron activation lags behind GABA neurons and is dependent on scratching of the itchy site. Optogenetic manipulations of VTA GABA neurons rapidly modulated scratching behaviors through encoding itch-associated aversion. In contrast, optogenetic manipulations of VTA DA neurons revealed their roles in sustaining recurrent scratching episodes through signaling scratching-induced reward. A similar dichotomy exists for the role of VTA in chronic itch. These findings advance understanding of circuit mechanisms of the unstoppable itch-scratch cycles and shed important insights into chronic itch therapy.