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Title: Structural and functional heterogeneity of striatal interneuron populations
Author: Garas, Farid
ISNI:       0000 0004 6495 8015
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2016
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The striatum is the largest nucleus of the basal ganglia, and acts as a point of convergence for thalamic, cortical and midbrain inputs. It is involved in both motor and associative forms of learning, and is composed of spiny projection neurons (SPNs) whose output along the so-called "direct pathway" and "indirect pathway" is modified by the activity of diverse sets of interneurons. Four "classical" or major classes of striatal interneuron can be identified according to the selective expression of the molecular markers parvalbumin (PV), calretinin (CR), nitric oxide synthase (NOS) or choline acetyltransferase (ChAT). Although the interneurons within a class are generally considered to be homogeneous in form and function, there is emerging evidence that some classes encompass multiple types of neuron, and that the heterogeneity in striatal interneurons extends beyond these four classes. Defining the extent of interneuron heterogeneity is important for understanding how the striatum processes distinct, topographically-organized inputs from the cortex and thalamus in order to govern a wide range of behaviors. To address these issues, a combination of immunofluorescence microscopy and stereological cell counting approaches was used in striatal tissue from rat, mouse and non-human primate. This was supplemented by in vivo recording and juxtacellular labelling of single neurons in rat. A first set of experiments showed that secretagogin (Scgn), a calcium-binding protein, is expressed by a large number of interneurons in the dorsal striatum of rat and primate, but not in the mouse. In all species tested, secretagogin was expressed by a subset of PV+ interneurons and a subset of CR+ interneurons in the dorsal striatum, but also labelled a group of interneurons that did not express any of the classical markers of striatal interneurons. A second set of experiments in the rat demonstrated that the selective co-expression of Scgn by PV+ interneurons delineates two topographically-, physiologically- and morphologically-distinct cell populations. These topographical differences in distribution were largely conserved in the primate caudate/putamen. In rats, PV+/Scgn+ and PV+/Scgn- interneurons differed significantly in their firing rates, firing patterns and phase-locking to cortical oscillations. The axons of PV+/Scgn+ interneurons were more likely to form appositions with the somata of direct pathway SPNs than indirect pathway SPNs, whereas the opposite was true for the axons of PV+/Scgn- interneurons. These two populations of GABAergic interneurons provide a potential substrate through which either of the striatal output pathways can be rapidly and selectively inhibited, and in turn mediate the expression of behavioral routines. A third set of experiments showed that CR+ interneurons of the dorsal striatum can be separated into three populations based on their molecular, topographical and morphological properties. Small-sized ("Type 3") CR+ interneurons co-expressed Scgn and were restricted in their distribution towards the rostro-medial poles of the striatum in both rats and primates. In rats, these neurons also expressed the transcription factor SP8, suggesting that they may be newly generated throughout adulthood. Large-sized, ("Type 1") CR+ interneurons did not express Scgn, but could be further distinguished by their expression of the transcription factor Lhx7. Medium-sized ("Type 2") CR+ interneurons did not express Scgn or Lhx7, and had heterogeneous electrophysiological properties in vivo. The expression of Scgn, but not other classical interneuron markers, identified a group of interneurons that were restricted in their distribution towards the ventro-medial aspects of the dorsal striatum. A fourth set of experiments showed that these neurons are also present in the core and the shell of the nucleus accumbens. Unlike the case of dorsal striatum, however, PV+ interneurons and CR+ interneurons of the nucleus accumbens did not co-express Scgn. Moreover, many of the interneuron populations studied had greater densities in the ventral striatum compared to the dorsal striatum, and had quantifiably strong biases in their distribution towards a variety of axes within both the core and the shell of the nucleus accumbens. These data thus highlight some major differences in the constituent elements of the microcircuits of dorsal striatum and nucleus accumbens. In conclusion, these studies have revealed a great deal of molecular, topographical, electrophysiological and structural heterogeneity within the interneuron populations of the striatum. As several of these interneuron populations were not evenly distributed throughout the striatum, this ultimately suggests that the microcircuit of the striatum is specialized according to regions that differ in their cortical, thalamic and dopaminergic inputs.
Supervisor: Sharott, Andrew ; Magill, Peter Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Interneurons ; Striatum ; Basal ganglia--Physiology ; Secretagogin ; Basal Ganglia