Somatosensory neurons densely innervate skin, our largest sensory organ. Adult skin continually remodels throughout the lifespan to maintain a protective barrier for our bodies. How sensory neurons maintain their peripheral endings in the face of continual turnover of their target tissue is not well understood. To address this gap in knowledge, I analyzed the temporal dynamics and mechanisms of structural plasticity of touch receptors in healthy adult skin. My studies focused on the terminals of Merkel-cell afferents in mouse touch domes. These two-part touch receptors comprise epithelial Merkel cells innervated by branching axons of fast-conducting sensory neurons. I show that Merkel cells and their afferents are structurally plastic over the course of hair growth in adults. These two components simplify during active hair growth, with fewer terminal neurites and fewer Merkel cells per touch dome at this stage compared with other phases of hair growth. Merkel-cell removal was observed with multiple molecular markers. Additionally, mice showed diminished touch-evoked behavior during hair growth compared with follicle quiescence. Next, I showed that Sarm1, a key effector of Wallerian degeneration, is not required for structural plasticity of Merkel cell-neurite complexes in young adulthood. Finally, I developed a technique to perform time-lapse in vivo imaging of identified Merkel cells and afferent terminals over the course of a month. These structures were highly plastic, with afferent terminals undergoing frequent growth and regression, as well as both Merkel cells and terminal branches being added or removed. Together, these studies reveal that peripheral nerve terminals undergo a previously unsuspected amount of structural plasticity in healthy tissue.

As animals explore and interact with their surroundings, information about their environment is constantly processed from sensory stimuli into perception. This information informs their behavior, decision-making, and understanding of their world. Information processing and perception have long been thought to be modulated by the behavior state of the animal (Cano et al. 2006; Niell and Stryker 2010; Polack et al. 2013; Poulet & Petersen, 2008; Briggs 2013, Schölvinck et al. 2015). Previous research has shown that behavior state strongly correlates with perceptual performance in a sensory discrimination task in rodents (McGinley et al. 2015, Schriver et al., 2018). However, the neural correlates behind this modulation of perception, information processing, and behavioral performance are not yet fully understood. The first part of this work investigates the relationship between cell-type specific spontaneous cortical activity and behavior state as defined by pupil-linked arousal. Spontaneous activity is essential in understanding the link between behavior state and information processing as it serves as the baseline state of activity prior to processing any stimuli information. Within the sensory cortices, excitatory and inhibitory neurons work in unison to dictate network activity. Three main classes of cortical inhibitory neurons are somatostatin-expressing neurons (SST), vasointestinal peptide-expressing neurons (VIP), and parvalbumin-expressing neurons (PV). These four cell types comprise the VIP disinhibitory circuit, in which VIP neurons disinhibit excitatory neurons by inhibiting PV and SST neurons. PV and SST neurons directly inhibit excitatory cells, so by suppressing their activity VIP neurons indirectly disinhibit excitatory cells. This circuit is a vitally important system used to modify excitatory activity in all cortical regions. The spontaneous activity of excitatory neurons and three classes of inhibitory neurons (somatostatin-expressing neurons (SST), vasointestinal peptide-expressing neurons (VIP), and parvalbumin-expressing neurons (PV)) was individually examined in this study. To visualize in-vivo spontaneous cortical activity, a genetically encoded calcium indicator (GCaMP) was expressed in the somatosensory cortex, and the population-level neural activity was imaged using fiber photometry. Despite the relationship between these neurons as defined by the VIP disinhibitory circuit, the spontaneous activity of excitatory, VIP, PV, and SST neurons was found to positively correlate with pupil size for all of these neuron types. This supports the theory that VIP and other interneuron types may be active in various functions, not just the disinhibition of excitatory cells. Pupil-evoked activity, or spontaneous activity during highly aroused states, was also found to positively correlate with pupil size for all cell types and had the strongest correlation for all correlation types. Therefore, pupil-linked arousal level relates to the increased activity of both excitatory and inhibitory cortical cells. While the first chapter focuses on spontaneous activity, the second focuses on stimulus-evoked activity. Stimulus-evoked activity in the somatosensory pathway can be caused by both internally generated stimuli and external stimuli. In the first step of sensory processing, the sensory receptors cannot distinguish between these two types of stimuli. However, the differentiation between the two is necessary in order to distinguish self from non-self. The motor-related timing signals that influence sensory processing and enable distinction between internally generated and external stimuli is termed corollary discharge. Where and how the mechanism of corollary discharge occurs in the somatosensory system is not well understood. To investigate corollary discharge in the somatosensory system, the neural activity in the somatosensory cortex was analyzed during internally generated stimuli and during delivery of external stimuli. More specifically, the activity in the vibrissa somatosensory cortex of rodents during self-induced whisking and during delivery of an air puff to the whiskers was examined. In the primary and secondary somatosensory cortex, excitatory activity was inhibited just prior to whisking and suppressed to a lower level during whisking in comparison to the activity level during air puff delivery. The three main classes of inhibitory neurons were studied to explore the possibility of local inhibition causing this suppression of the excitatory signal during whisking. VIP, PV and SST neurons all exhibited a similar pre-whisking inhibition and suppression of activity during whisking, eliminating the possibility of their role in pre-whisking inhibition and whisking activity suppression. Other regions involved in the somatosensory pathway and sensorimotor processing, such as the thalamus and motor cortex, were also found to not contribute to pre-whisking inhibition or whisking activity suppression as they were also found to exhibit the same phenomenon. After ruling out cortical inhibitory neurons and somatosensory regions in the involvement of corollary discharge, external higher-order regions were investigated. Previous studies on the sources of corollary discharge in the cerebellum have shown corollary discharge signals originate from coordination of several different higher-order brain regions (Person A., 2019). To determine these potential regions for somatosensory corollary discharge, viral tracing vectors were used to locate regions with long-range inhibitory projections to the somatosensory cortex. The globus pallidus (GP) was first investigated due to its role in voluntary movement and projections to the frontal cortex (Saunders et al. 2015). However, no inhibitory projections from the GP to the somatosensory cortex were found. The striatum, which is mainly GABAergic (and therefore inhibitory), also seemed to be a likely candidate. Preliminary tracing results suggest the striatum does have inhibitory projections to the somatosensory cortex. Further studies of both retrograde and anterograde tracing must be performed to confirm this finding. Nonetheless, the evidence of corollary discharge as seen through pre-whisking inhibition and the suppression of activity during whisking in S1, S2, thalamus, and motor cortex is a novel finding and opens up many avenues for further research.