Loss of striatal tyrosine‐hydroxylase interneurons impairs instrumental goal‐directed behavior

Abstract

The striatum mediates a broad range of cognitive and motor functions. Within the striatum, recently discovered tyrosine hydroxylase expressing interneurons (THINs) provide a source of intrastriatal synaptic connectivity that is critical for regulating striatal activity, yet the role of THIN's in behavior remains unknown. Given the important role of the striatum in reward‐based behaviors, we investigated whether loss of striatal THINs would impact instrumental behavior in mice. We selectively ablated striatal THINs in TH‐Cre mice using chemogenetic techniques, and then tested THIN‐lesioned or control mice on three reward‐based striatal‐dependent instrumental tests: (a) progressive ratio test; (b) choice test following selective‐satiety induced outcome devaluation; (c) outcome reinstatement test. Both striatal‐THIN‐lesioned and control mice acquired an instrumental response for flavored food pellets, and their behavior did not differ in the progressive ratio test, suggesting intact effort to obtain rewards. However, striatal THIN lesions markedly impaired choice performance following selective‐satiety induced outcome devaluation. Unlike control mice, THIN‐lesioned mice did not adjust their choice of actions following a change in outcome value. In the outcome reinstatement test THIN‐lesioned and control mice showed response invigoration by outcome presentation, suggesting the incentive properties of outcomes were not disrupted by THIN lesions. Overall, we found that striatal THIN lesions selectively impaired goal‐directed behavior, while preserving motoric and appetitive behaviors. These findings are the first to describe a function of striatal THINs in reward‐based behavior, and further illustrate the important role for intrastriatal interneuronal connectivity in behavioral functions ascribed to the striatum more generally.

Methylation of the tyrosine hydroxylase gene is dysregulated by cocaine dependence in the human striatum

“…Notably, a cluster of CpGs within the body of the TH gene was among the top most hypermethylated loci in our analysis (9.17%, Table 1 ). Since TH is a necessary component of dopamine synthesis and has a known relationship with reward-driven behaviors ( Kaminer et al., 2019 ; Logan et al., 2019 ) we were immediately struck by its potential importance. Interestingly, TH was also identified among the short list of DMRs that were shared between the current study and our previous work in the caudate nucleus (orange data points Figures 1 B and Table 2 ), where the exact same cluster of CpGs was differentially methylated in the same direction, and similar to a magnitude (9.09%).…”

“…Interestingly, TH was also identified among the short list of DMRs that were shared between the current study and our previous work in the caudate nucleus (orange data points Figures 1 B and Table 2 ), where the exact same cluster of CpGs was differentially methylated in the same direction, and similar to a magnitude (9.09%). Notably, up to 3% of GABAergic interneurons within the striatum express TH, and although these cells do not appear to be dopaminergic, they have been shown to play a role in motivational behavior in rodents ( Ibáñez-Sandoval et al., 2010 ; Kaminer et al., 2019 ; Savell et al., 2020 ). The TH DMR is comprised of 3 CpGs within a CpG island in the eighth and ninth exon of TH, and we chose to further investigate this locus in the context of human cocaine neurobiology.…”

Striatal cholinergic transmission. Focus on nicotinic receptors’ influence in striatal circuits

“…Despite their rarity, we and others have demonstrated that striatal GABAergic interneurons receiving nicotinic inputs are important in the regulation striatal-related behaviors such as prepulse-inhibition (Assous et al, 2017) or goal-directed behaviors (Assous, 2020;Holly et al, 2019;Kaminer et al, 2019). However, the role of their interconnections with cholinergic interneurons has yet to be explored.…”

Neural substrates of habit

“…Striatal microcircuits are also regulated by tyrosine hydroxylase‐expressing interneurons (THINs) that receive excitatory thalamic and cortical input, as well as integrate dopaminergic and cholinergic signaling (Ibáñez‐Sandoval et al, ; Ibáñez‐Sandoval, Xenias, Tepper, & Koós, ). Kaminer et al () found that THIN lesions throughout the dorsal striatum do not impair motivation to lever press for a food reward in the progressive ratio test, in which the response requirement increases for each successive reward, but do produce insensitivity to outcome devaluation (Kaminer et al, ). This impairment in goal‐directed behavior was found to correlate with THIN lesions restricted to the more posterior striatum (Kaminer et al, ), which corresponds with the necessity of the posterior DMS, but not the anterior DMS, for goal‐directed behavior (Yin, Ostlund, et al, ).…”

“…Kaminer et al () found that THIN lesions throughout the dorsal striatum do not impair motivation to lever press for a food reward in the progressive ratio test, in which the response requirement increases for each successive reward, but do produce insensitivity to outcome devaluation (Kaminer et al, ). This impairment in goal‐directed behavior was found to correlate with THIN lesions restricted to the more posterior striatum (Kaminer et al, ), which corresponds with the necessity of the posterior DMS, but not the anterior DMS, for goal‐directed behavior (Yin, Ostlund, et al, ). A potential means by which THINs affect behavioral control is via the integration of cholinergic signaling.…”