The role of electrical synapses in neural dynamics involved in sleep/wake and sensory perception

The broad objective of this proposal is to investigate the brain-region-specific role of the neuronal gap-
junction protein, connexin 36 (Cx36), in the regulation of sleep-wake behavioral state- and stimulus-specific
cortical oscillations. Gap junction coupling leads to the formation of electrical synapses which promote
neuronal synchronization; influencing network-wide oscillations which are likely involved in sensory and
cognitive functions. Aberrant oscillatory activity and network connectivity underlie a wide range of sleep
disorders, and neurological/neuropsychiatric disorders. The thalamic reticular nucleus (TRN) is a key
component of cortico-thalamic circuitry and is critical for regulation of cortical oscillatory activity associated with
sleep/wake state and sensory processing. GABAergic neurons of the TRN work in concert to control the
activity of thalamic relay neurons, influencing cortical oscillatory activity. A key feature of the TRN is that local
inter-neuronal communication occurs exclusively via Cx36 containing electrical synapses. While the functional
contributions of various receptors and ion channels in TRN have been widely studied in association with its role
in thalamocortical activity, the role of electrical synapses and gap junction proteins is underexplored. Our
preliminary findings along with prior studies have shown that disruption of Cx36 globally can impair the
synchronization of neural rhythms. However, the role of Cx36 electrical synapses specifically in the TRN has
yet to be examined. The TRN regulates cortical oscillatory activity in delta (0.5-4 Hz), sigma (10-15 Hz; sleep
spindles) range during sleep, and gamma (30-80 Hz) during wakefulness and wake-associated sensory
processes. Therefore, investigating the importance of Cx36 within TRN is key towards understanding how the
TRN neurons communicate locally to coordinate modulation of distal cortical oscillatory activity. Here we
propose to test the hypothesis that the TRN electrical synapses containing Cx36 are essential for modulation
of cortical network dynamics. Towards this goal, we propose to use the state-of-the-art, highly efficient gene
editing technique, clustered regularly interspaced short palindromic repeats (CRISPR) - and its associated
protein - Cas9, to knockdown the Cx36 protein, in vivo, specifically in parvalbumin positive neurons of the TRN.
Utilizing this model, we will examine the role of the TRN-specific Cx36 expression on 1) cortical oscillatory
activity associated with sleep and wakefulness, and 2) regulation of sensory processing via alteration of
functional connectivity between first order and higher order regions of the cortex. 3) Finally, we will rescue the
deficits caused by Cx36KO by reintroducing Cx36 gene in parvalbumin neurons of the TRN. Successful
completion of the proposed studies will provide insight into the TRN- a uniquely composed brain structure and
GABAergic nucleus where gap-junction proteins are predominantly responsible for inter-neuronal
communications, and its overall influence in sleep- wake and the homeostatic sleep-associated as well as task-
evoked cortical oscillations.

Grant Number: 5I01BX006105-02
NIH Institute/Center: VA
Principal Investigator: RADHIKA BASHEER