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Graphical Abstract Highlights d Excitatory NPYR1 Cre (Y1 Cre ) neurons are required for mechanical itch transmission d Spinal Y1 Cre neurons receive LTMR input and mediate light punctate touch d NPY::Cre interneurons inhibit Y1-expressing neurons in the dorsal horn d NPY signaling via dorsal horn Y1-expressing neurons gates mechanical itch In Brief Acton et al. identify the excitatory neurons in the dorsal spinal cord that drive mechanical itch. These cells mediate responses to light punctate touch and are inhibited by neuropeptide Y (NPY)::Cre interneurons. Light touch sensitivity and mechanical itch responses are gated by NPY signaling mediated by Y1-expressing neurons in the dorsal horn. Mechanical itch Disrupted inhibitory gating Normal inhibitory gating Y1 + Low-threshold mechanoreceptors NPY + Normal touch discrimination NPY Y1 + NPY + Mechanical itch NPY Low-threshold mechanoreceptors SUMMARYAcute itch can be generated by either chemical or mechanical stimuli, which activate separate pathways in the periphery and spinal cord. While substantial progress has been made in mapping the transmission pathway for chemical itch, the central pathway for mechanical itch remains obscure. Using complementary genetic and pharmacological manipulations, we show that excitatory neurons marked by the expression of the neuropeptide Y1 receptor (Y1 Cre neurons) form an essential pathway in the dorsal spinal cord for the transmission of mechanical but not chemical itch. Ablating or silencing the Y1 Cre neurons abrogates mechanical itch, while chemogenetic activation induces scratching. Moreover, using Y1 conditional knockout mice, we demonstrate that endogenous neuropeptide Y (NPY) acts via dorsalhorn Y1-expressing neurons to suppress light punctate touch and mechanical itch stimuli. NPY-Y1 signaling thus regulates the transmission of innocuous tactile information by establishing biologically relevant thresholds for touch discrimination and mechanical itch reflexes.

The primary motor cortex has an important role in the precise execution of learned motor responses. During motor learning, synaptic efficacy between sensory and primary motor cortical neurons is enhanced, possibly involving long-term potentiation and N-methyl-D-aspartate (NMDA)-specific glutamate receptor function. To investigate whether NMDA receptor in the primary motor cortex can act as a coincidence detector for activity-dependent changes in synaptic strength and associative learning, here we generate mice with deletion of the Grin1 gene, encoding the essential NMDA receptor subunit 1 (GluN1), specifically in the primary motor cortex. The loss of NMDA receptor function impairs primary motor cortex long-term potentiation in vivo. Importantly, it impairs the synaptic efficacy between the primary somatosensory and primary motor cortices and significantly reduces classically conditioned eyeblink responses. Furthermore, compared with wild-type littermates, mice lacking primary motor cortex show slower learning in Skinner-box tasks. Thus, primary motor cortex NMDA receptors are necessary for activity-dependent synaptic strengthening and associative learning.

Neuropeptide Y (NPY) plays an important role in stress, anxiety, obesity, and energy homeostasis via activation of NPY-Y1 receptors (Y1Rs) in the brain. However, global knockout of the Npy1r gene has low or no impact on anxiety and body weight. To uncover the role of limbic Y1Rs, we generated conditional knockout mice in which the inactivation of the Npy1r gene was restricted to excitatory neurons of the forebrain, starting from juvenile stages (Npy1r rfb ). Npy1r rfb mice exhibited increased anxiety and reduced body weight, less adipose tissue, and lower serum leptin levels. Npy1r rfb mutants also had a hyperactive hypothalamic-pituitaryadrenocortical axis, as indicated by higher peripheral corticosterone and higher density of NPY immunoreactive fibers and corticotropin releasing hormone immunoreactive cell bodies in the paraventricular hypothalamic nucleus. Importantly, through fostering experiments, we determined that differences in phenotype between Npy1r rfb and Npy1r 2lox mice became apparent when both genotypes were raised by FVB/J but not by C57BL/6J dams, suggesting that limbic Y1Rs are key targets of maternal care-induced programming of anxiety and energy homeostasis. where it is involved in the regulation of anxiety, stress reactions, energy balance, circadian rhythms, and cognition (1-3). Clinical studies suggest that NPY plays an important role in the response to stress and in psychiatric disorders (4). In humans, NPY haploinsufficiency is correlated with characteristic brain responses to emotional and stress challenges and with trait anxiety (5). Intracerebroventricular injection of NPY reduces both anxiety-and stress-related behavior in several animal models, an effect that is primarily mediated by Y1 receptors (Y1Rs) expressed in amygdala, hippocampus, and locus coeruleus (6-9). The implications of a role of endogenous NPY in acting via Y1R to control emotionality, mood, and stress reactions have been probed with Y1R-selective antagonists and antisense oligonucleotides (1). NPY exerts its anxiolytic-like effect in the brain via interactions with the hypothalamic-pituitaryadrenocortical (HPA) axis and corticosteroids. Indeed, a functional antagonism between NPY and corticotropin releasing hormone (CRH) has been demonstrated in various CNS nuclei along the stress/anxiety circuits (10).In addition to its crucial role in emotional behavior, NPY potently stimulates feeding, reduces energy expenditure, and induces obesity via the activation of Y1R expressed in the hypothalamus (1). However, global Npy1r gene knockout mice showed only minor deficiencies in energy homeostasis, feeding, and anxiety (11)(12)(13)(14).To study the function of Y1R expressed in the limbic system and to exclude effects induced by the Npy1r gene inactivation in early development, we restricted the ablation of Y1R to excitatory neurons in the postnatal forebrain of mice by using the Cre-loxP system (Fig. 1A). In addition, because early postnatal environment can modulate NPY levels (15), gene-targeted pups were reared by two diffe...