Itch-induced scratching is an evolutionarily conserved behavioral response that protects organisms from potential parasites/irritants in their immediate vicinity. How the exposure to a pruritogen is translated to the perception of itch and how that perception drives scratching directed towards the site of exposure remains poorly understood. In this review, we focus on the recent findings that shed light on the neural pathways in the brain that underlie itch-induced scratching. We compare the molecularly defined itch pathways with the known pain circuits as they have anatomical and functional overlap. We review the roles played by the neurons in the spinoparabrachial pathway—comprising of the neurons in the spinal cord and the parabrachial nucleus (PBN), which acts as a hub for transmitting itch information across the brain. Lastly, we deliberate on scratching as a behavioral measure of the intensity of itch and its implication in unraveling the underlying supraspinal mechanisms. In summary, we provide a resource on the recent advances and discuss a path forward on our understanding of the neural circuits for itch.

Stress is a powerful modulator of pain. Specifically, acute stress due to physical restraint facilitates stress-induced analgesia (SIA). However, where and how acute stress and pain pathways interface in the brain must be better understood. Here, we describe how the lateral septum (LS), a forebrain limbic nuclei, facilitates SIA through its downstream targets in the lateral hypothalamus (LH). We show that the LS→LH circuitry is sufficient to drive analgesia and is required for SIA. Further, we reveal that the LS→LH pathway is opioid-dependent and modulates pain through the pro-nociceptive neurons in the rostral ventromedial medulla (RVM). Remarkably, we found that the LS neurons are inhibitory, are recruited specifically when the mice struggle to escape under restraint, and, in turn, inhibit excitatory LH neurons. As a result, the RVM neurons downstream of LH are disengaged when the mice try to escape, thus suppressing nociception. Next, our data indicate that the efforts to escape are communicated by the lateral periaqueductal gray (lPAG) to the LS and activation of the upstream lPAG→LS circuit phenocopies LS→LH activation and results in analgesia. Thus, we have revealed a poly-synaptic pathway that can transform escape behavior in mice under restraint to acute stress and resultant analgesia.

Objectively measuring animal behavior is key to understanding the neural circuits underlying pain. Recent progress in machine vision has presented us with unprecedented scope in behavioral analysis. Here, we apply DeeplabCut (DLC) to dissect mouse behavior on the thermal-plate test - a commonly used paradigm to ascertain supraspinal contributions to noxious thermal sensation and pain hypersensitivity. We determine the signature characteristics of the pattern of mouse movement and posture in 3D in response to a range of temperatures from innocuous to noxious on the thermal-plate test. Next, we test how acute chemical and chronic inflammatory injuries sensitize mouse behaviors. Repeated exposure to noxious temperatures on the thermal-plate can induce learning, and in this study, we design a novel assay and formulate an analytical pipeline that will facilitate the dissection of plasticity mechanisms in pain circuits in the brain. Last, we record and test how activating Tacr1 expressing PBN neurons - a population responsive to sustained noxious stimuli- affects mouse behavior on the thermal plate test. Taken together, we demonstrate that by tracking a single body part of a mouse, we can reveal the behavioral signatures of mice exposed to noxious surface temperatures, report the alterations of the same when injured, and determine if a molecularly and anatomically defined pain responsive circuit plays a role in the reflexive hypersensitivity to thermal pain.