Neurons of the intralaminar thalamus, including central lateral (CL) and parafascicular (Pf) nuclei, innervate the cortex and striatum and are important for cognitive, sensory, and motor processes. We tested the hypothesis that CL and Pf neurons provide functionally distinct inputs to the striatum. We performed recordings of single CL and Pf neurons in anesthetized rats and, after juxtacellularly labeling the neurons, their somatodendritic features and synaptic connections were characterized.All CL neurons (n ϭ 31) discharged classic low-threshold Ca 2ϩ spike bursts during cortical slow-wave activity in vivo. In contrast, Pf neurons (n ϭ 52) rarely fired such bursts, but instead discharged groups of spikes at relatively low frequencies. The activity of CL and Pf neurons was often temporally coupled to cortical slow oscillations. Identified CL neurons possessed archetypal "bushy" dendrites and preferentially established synapses with dendritic spines (91% of synapses) of striatal projection neurons. Pf neurons possessed "reticular-like" dendrites, and, on average, preferentially established synapses with dendritic shafts (63%) in striatum, although connectivity was markedly heterogeneous across neurons. Two of the six Pf neurons studied exclusively targeted dendritic shafts, whereas another neuron almost exclusively (97%) targeted spines. The remaining three neurons preferentially targeted dendritic shafts (53-70%).Thus, the fundamental properties of CL and Pf neurons differ (the latter do not express the typical operational principles of thalamic relay neurons), and they provide different temporally patterned inputs to distinct striatal targets. This mechanistic diversity likely underpins the transmission of specific and discrete information from intralaminar thalamic nuclei to striatal and cortical targets.

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In drug users, drug-related cues alone can induce dopamine release in the dorsal striatum. Instructive cues activate inputs to the striatum from both dopaminergic and cholinergic neurons, which are thought to work together to support motor learning and motivated behaviors. Imbalances in these neuromodulatory influences can impair normal action selection and might thus contribute to pathologically repetitive and compulsive behaviors such as drug addiction. Dopamine and acetylcholine can have either antagonistic or synergistic effects on behavior, depending on the state of the animal and the receptor signaling systems at play. Semi-synchronized activation of cholinergic interneurons in the dorsal striatum drives dopamine release via presynaptic nicotinic acetylcholine receptors located on dopamine terminals. Nicotinic receptor blockade is known to diminish abnormal repetitive behaviors (stereotypies) induced by psychomotor stimulants. By contrast, blockade of postsynaptic acetylcholine muscarinic receptors in the dorsomedial striatum exacerbates drug-induced stereotypy, exemplifying how different acetylcholine receptors can also have opposing effects. Although acetylcholine release is known to be altered in animal models of drug addiction, predicting whether these changes will augment or diminish drug-induced behaviors thus remains a challenge. Here, we measured amphetamine-induced stereotypy in BAC transgenic mice that have been shown to overexpress the vesicular acetylcholine transporter (VAChT) with consequent increased acetylcholine release. We found that drug-induced stereotypies, consisting of confined sniffing and licking behaviors, were greatly increased in the transgenic mice relative to sibling controls, as was striatal VAChT protein. These findings suggest that VAChT-mediated increases in acetylcholine could be critical in exacerbating drug-induced stereotypic behaviors and promoting exaggerated behavioral fixity.