Date on Master's Thesis/Doctoral Dissertation

5-2020

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Anatomical Sciences and Neurobiology

Degree Program

Anatomical Sciences and Neurobiology, PhD

Committee Chair

Guido, William

Committee Co-Chair (if applicable)

Bickford, Martha

Committee Member

Bickford, Martha

Committee Member

Borghuis, Bart

Committee Member

Gregg, Ron

Committee Member

McCall, Maureen

Author's Keywords

thalamus; vision; circuit; geniculate; inhibition; mouse

Abstract

The thalamic reticular nucleus (TRN) is an interface between thalamus and cortex that regulates thalamocortical rhythms and modulates sensory processing. Thalamocortical axon collaterals provide feedforward excitatory input onto GABAergic TRN neurons, which in turn convey feedback inhibition to dorsal thalamus. Here we used the mouse visual system to study the organization, pattern of innervation and functional responses between TRN and the dorsal lateral geniculate nucleus (dLGN). We used genetically modified mice to target components of this feedback loop (feedforward: CRH-Cre; feedback: GAD65 or SST-Cre) and we created Math 5-/- strains to examine the impact of visual deaffrentation in these circuits. We conducted both anterograde and retrograde neural tracing to assess the organization of sensory feedforward projections in TRN and established that the configuration we observed in adults is present at perinatal ages in both WT and Math 5-/- mice. To examine the formation and functional maturation of intrathalamic circuits, we used confocal microscopy to examine when terminals arrive, and electrophysiologic recordings during optogenetic stimulation in acute thalamic slice preparations to assess the maturation of functional responses. Although thalamocortical projections were present in TRN at birth, feedforward circuits emerged during the second postnatal week and continued to mature through the third week. Feedback projections were established during the first postnatal week but functional responses continued to develop through the fourth postnatal week. In Math 5-/- mice, feedforward projections were unchanged compared to WT but feedback terminals arrived at earlier ages and exhibited more synaptic suppression at higher rates of stimulation. In adults, ultrastructural analysis of feedback projections revealed that TRN terminals only form synapses with relay neurons, a result confirmed by electrophysiological recordings. Recordings in acute slices established that tonic TRN activation hyperpolarized and suppressed relay neuron firing in a frequency-dependent manner. The impact of frequency was confirmed in vivo in an awake behaving head fixed preparation. Together, these experiments advance our understanding of the synaptic nature of TRN inhibition of dLGN. They also establish the developmental pattern of connectivity between dLGN and TRN, both in the presence and absence of retinal signaling.

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