Preferential Modulatory Action of 5-HT2A Receptors on the Dynamic Regulation of Basal Ganglia Circuits.

In rodents, cortical information is transferred to the substantia nigra pars reticulata (SNr) through motor and medial prefrontal (mPF) basal ganglia (BG) circuits implicated in motor and cognitive/motivational behaviors, respectively. The serotonergic 5-HT2A receptors are located in both of these neuronal networks, displaying topographical differences with a high expression in the associative/limbic territories, and a very low expression in the subthalamic nucleus. This study investigated whether the stimulation of 5-HT2A receptors could have a specific signature on the dynamic regulation of BG circuits, preferentially modulating the mPF information processing through trans-striatal pathways. We performed in vivo single-unit extracellular recordings to assess the effect of the 5-HT2A agonist TCB-2 on the spontaneous and cortically evoked activity of lateral and medial SNr neurons in male rats (involved in motor and mPF circuits, respectively). TCB-2 (50-200 µg/kg, i.v.) increased the basal firing rate and enhanced the cortically evoked inhibitory response of medial SNr neurons (transmission through the direct striato-nigral pathway). A prior administration of the preferential 5-HT2A receptor antagonist MDL11939 (200 µg/kg, i.v.) did not modify any electrophysiological parameter, but occluded TCB-2-induced effects. In animals treated with the 5-HT synthesis inhibitor pCPA (4-chloro-dl-phenylalanine methyl ester hydrochloride), TCB-2 failed to induce the above-mentioned effects, thus suggesting the contribution of endogenous 5-HT. However, the mobilization of 5-HT induced by the acute administration of fluoxetine (10 mg/kg, i.p.) did not mimic the effects triggered by TCB-2. Overall, these data suggest that 5-HT2A receptors have a preferential modulatory action on the dynamic regulation of BG circuitry.SIGNIFICANCE STATEMENT Motor and medial prefrontal (mPF) basal ganglia (BG) circuits play an important role in integrative brain functions like movement control or cognitive/motivational behavior, respectively. Although these neuronal networks express 5-HT2A receptors, the expression is higher in associative/limbic structures than in the motor ones. We show a topographical-dependent dissociation in the effects triggered by the 5HT2A agonist TCB-2, which specifically increases the medial substantia nigra pars reticulata neuron activity and has a preferential action on mPF information processing through the striato-nigral direct pathway. These are very likely to be 5-HT2A receptor-mediated effects that require mobilization of the endogenous 5-HT system. These findings provide evidence about the specific signature of 5-HT2A receptors on the dynamic regulation of BG circuits.

Lateralization of brain activity pattern during unilateral movement in Parkinson's disease.

We investigated the lateralization of brain activity pattern during performance of unilateral movement in drug-naïve Parkinson's disease (PD) patients with only right hemiparkinsonian symptoms. Functional MRI was obtained when the subjects performed strictly unilateral right hand movement. A laterality index was calculated to examine the lateralization. Patients had decreased activity in the left putamen and left supplementary motor area, but had increased activity in the right primary motor cortex, right premotor cortex, left postcentral gyrus, and bilateral cerebellum. The laterality index was significantly decreased in PD patients compared with controls (0.41 ± 0.14 vs. 0.84 ± 0.09). The connectivity from the left putamen to cortical motor regions and cerebellum was decreased, while the interactions between the cortical motor regions, cerebellum, and right putamen were increased. Our study demonstrates that in early PD, the lateralization of brain activity during unilateral movement is significantly reduced. The dysfunction of the striatum-cortical circuit, decreased transcallosal inhibition, and compensatory efforts from cortical motor regions, cerebellum, and the less affected striatum are likely reasons contributing to the reduced motor lateralization. The disruption of the lateralized brain activity pattern might be a reason underlying some motor deficits in PD, like mirror movements or impaired bilateral motor coordination.

Striatonigrostriatal Spirals in Addiction.

A biological reward system is integral to all animal life and humans are no exception. For millennia individuals have investigated this system and its influences on human behavior. In the modern day, with the US facing an ongoing epidemic of substance use without an effective treatment, these investigations are of paramount importance. It is well known that basal ganglia contribute to rewards and are involved in learning, approach behavior, economic choices, and positive emotions. This review aims to elucidate the physiological role of striatonigrostriatal (SNS) spirals, as part of basal ganglia circuits, in this reward system and their pathophysiological role in perpetuating addiction. Additionally, the main functions of neurotransmitters such as dopamine and glutamate and their receptors in SNS circuits will be summarized. With this information, the claim that SNS spirals are crucial intermediaries in the shift from goal-directed behavior to habitual behavior will be supported, making this circuit a viable target for potential therapeutic intervention in those with substance use disorders.

Deep Brain Stimulation for Movement Disorders of Basal Ganglia Origin: Restoring Function or Functionality?

Deep brain stimulation (DBS) is highly effective for both hypo- and hyperkinetic movement disorders of basal ganglia origin. The clinical use of DBS is, in part, empiric, based on the experience with prior surgical ablative therapies for these disorders, and, in part, driven by scientific discoveries made decades ago. In this review, we consider anatomical and functional concepts of the basal ganglia relevant to our understanding of DBS mechanisms, as well as our current understanding of the pathophysiology of two of the most commonly DBS-treated conditions, Parkinson's disease and dystonia. Finally, we discuss the proposed mechanism(s) of action of DBS in restoring function in patients with movement disorders. The signs and symptoms of the various disorders appear to result from signature disordered activity in the basal ganglia output, which disrupts the activity in thalamocortical and brainstem networks. The available evidence suggests that the effects of DBS are strongly dependent on targeting sensorimotor portions of specific nodes of the basal ganglia-thalamocortical motor circuit, that is, the subthalamic nucleus and the internal segment of the globus pallidus. There is little evidence to suggest that DBS in patients with movement disorders restores normal basal ganglia functions (e.g., their role in movement or reinforcement learning). Instead, it appears that high-frequency DBS replaces the abnormal basal ganglia output with a more tolerable pattern, which helps to restore the functionality of downstream networks.