Activity-dependent cell survival in the adult somatosensory dorsal horn: Implications for sensorimotor behaviors during aging

About This Grant

Project Summary/Abstract The somatosensory dorsal horn comprises an array of neuronal populations that receive sensory information from the skin. In recent years, the development of transcriptomic and intersectional genetic tools has allowed the characterization of these populations in young adult animals with respect to their distinct molecular identities and functional roles in the processing and transmission of touch, pain and itch information. Preliminary data indicate that the survival of neurons in the dorsal horn of adult mice is dependent on excitatory input from touch receptors in the skin. This has implications for the processing of somatosensory information during aging, in which the transmission of touch information is impaired by demyelination and by the loss of mechanosensory end organs including Merkel cells (Feng et al., 2018). Chronic silencing Merkel cells in young adult Atoh1CreERT2; Piezo2f/f mice results in the apoptotic loss of excitatory and inhibitory dorsal horn neurons by 20-25%, with some molecularly defined populations being highly susceptible to cell death and others being resistant. A similar pattern of neuronal cell loss by apoptosis is detected in the dorsal horn of 2-year-old mice. The objective of this proposal is to characterize activity-dependent changes to the cellular composition of the spinal dorsal horn during aging and to determine the functional consequences of dorsal horn remodeling for the execution of sensorimotor behaviors as animals age. These experiments will (1) selectively perturb activity in different classes of cutaneous afferent to identify inputs that support cell survival in adult mice; (2) identify dorsal horn populations, defined by molecular profile, that are maintained by input from the periphery; (3) identify molecularly defined dorsal horn populations that are reduced in size during aging; (4) test the hypothesis that the reduction in the size of the neuronal population marked by expression of Cck and Sst that occurs following the loss of input from Merkel cells during aging impairs the execution of skilled locomotor and other sensorimotor behaviors; Cck+/Sst+ neurons are proposed to relay cutaneous tactile information to ventral horn motor circuits. Activity-dependent remodeling of the cellular landscape of the dorsal horn has broad implications for the processing of touch, pain and itch information during aging, as well as in conditions in which peripheral input is impaired, such as the peripheral neuropathies that arise from diabetes mellitus and chemotherapy treatment. This proposal will advance our understanding of how somatosensory processing changes across the lifespan and will determine the contribution of these changes to age-related sensorimotor dysfunction. Furthermore, it will likely inform therapeutic strategies for the treatment of somatosensory and sensorimotor disorders in older populations.