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IntroductionNeuropathic pain is characterized by mechanical allodynia and thermal (heat and cold) hypersensitivity, yet the underlying neural mechanisms remain poorly understood. MethodsUsing chemogenetic excitation and inhibition, we examined the role of inhibitory interneurons in the basolateral amygdala (BLA) in modulating pain perception following nerve injury. ResultsChemogenetic excitation of parvalbumin-positive (PV⁺) interneurons significantly alleviated mechanical allodynia but had minimal effects on thermal hypersensitivity. However, inhibition of PV⁺interneurons did not produce significant changes in pain sensitivity, suggesting that reductions in perisomatic inhibition do not contribute to chronic pain states. In contrast, bidirectional modulation of somatostatin-positive (SST⁺) interneurons influenced pain perception in a modality-specific manner. Both excitation and inhibition of SST⁺interneurons alleviated mechanical allodynia, indicating a potential compensatory role in nociceptive processing. Additionally, SST⁺neuron excitation reduced cold hypersensitivity without affecting heat hypersensitivity, whereas inhibition improved heat hypersensitivity but not cold responses. DiscussionOur findings suggest that, in addition to PV⁺neurons, SST⁺interneurons in the BLA play complex roles in modulating neuropathic pain following nerve injury and may serve as a potential target for future neuromodulation interventions in chronic pain management. 

Abstract Many cognitive and sensory processes are characterized by strong relationships between the timing of neuronal spiking and the phase of ongoing local field potential oscillations. The coupling of neuronal spiking in neocortex to the phase of alpha oscillations (8-12 Hz) has been well studied in nonhuman primates but remains largely unexplored in other mammals. How this alpha modulation of spiking differs between brain areas and cell types, as well as its role in sensory processing and decision making, are not well understood. We used Neuropixels 1.0 probes to chronically record neural activity from somatosensory cortex, prefrontal cortex, striatum, and amygdala in mice performing a whisker-based selective detection task. We observed strong spontaneous alpha modulation of single-neuron spiking activity during inter-trial intervals while mice performed the task. The prevalence and strength of alpha phase modulation differed significantly across regions and between cell types. Phase modulated neurons exhibited stronger responses to both go and no-go stimuli, as well as stronger motor- and reward-related changes in firing rate, than their unmodulated counterparts. The increased responsiveness of phase modulated neurons suggests they are innervated by more diverse populations. Alpha modulation of neuronal spiking during baseline activity also correlated with task performance. In particular, many neurons exhibited strong alpha modulation before correct trials, but not before incorrect trials. These data suggest that dysregulation of spiking activity with respect to alpha oscillations may characterize lapses in attention. 

The noradrenergic and cholinergic modulation of functionally distinct regions of the brain has become one of the primary organizational principles behind understanding the contribution of each system to the diversity of neural computation in the central nervous system. Decades of work has shown that a diverse family of receptors, stratified across different brain regions, and circuit-specific afferent and efferent projections play a critical role in helping such widespread neuromodulatory systems obtain substantial heterogeneity in neural information processing. This review briefly discusses the anatomical layout of both the noradrenergic and cholinergic systems, as well as the types and distributions of relevant receptors for each system. Previous work characterizing the direct and indirect interaction between these two systems is discussed, especially in the context of higher order cognitive functions such as attention, learning, and the decision-making process. Though a substantial amount of work has been done to characterize the role of each neuromodulator, a cohesive understanding of the region-specific cooperation of these two systems is not yet fully realized. For the field to progress, new experiments will need to be conducted that capitalize on the modular subdivisions of the brain and systematically explore the role of norepinephrine and acetylcholine in each of these subunits and across the full range of receptors expressed in different cell types in these regions.