Neuromodulation of deep brain structures (deep brain stimulation) is the current surgical procedure for treatment of Parkinson's disease (PD). Less studied is the stimulation of cortical motor areas to treat PD symptoms, although also known to alleviate motor disturbances in PD. We were able to show that optogenetic activation of secondary (M2) motor cortex improves motor functions in dopamine-depleted male mice. The stimulated M2 cortex harbors glutamatergic pyramidal neurons that project to subcortical structures, critically involved in motor control, and makes synaptic contacts with dopaminergic neurons. Strikingly, optogenetic activation of M2 neurons or axons into the dorsomedial striatum increases striatal levels of dopamine and evokes locomotor activity. We found that dopamine neurotransmission sensitizes the locomotor behavior elicited by activation of M2 neurons. Furthermore, combination of intranigral infusion of glutamatergic antagonists and circuit specific optogenetic stimulation revealed that behavioral response depended on the activity of M2 neurons projecting to SNc. Interestingly, repeated M2 stimulation combined with L-DOPA treatment produced an unanticipated improvement in working memory performance, which was absent in control mice under L-DOPA treatment only. Therefore, the M2-basal ganglia circuit is critical for the assembly of the motor and cognitive function, and this study demonstrates a therapeutic mechanism for cortical stimulation in PD that involves recruitment of long-range glutamatergic projection neurons.

Parkinson's disease is a progressive neurodegenerative movement disorder that happens due to the loss of dopaminergic neurons in the substantia nigra. The deficiency of dopamine in the basal nuclei drives cardinal motor symptoms such as bradykinesia and hypokinesia. The current protocol describes the cylinder test, which is a relatively simple behavioral assessment that evaluates the motor deficits upon unilateral degeneration of the nigrostriatal pathway in experimental models of Parkinson's disease. Since dopamine-depleted mice exhibit the preferential use of the forelimb ipsilateral to the lesion, here researchers perform the cylinder test to investigate the therapeutic effects of antiparkinsonian treatments on the performance of the contralateral (injured) limb.

The incoming signals from injured sensory neurons upon peripheral inflammation are processed in the dorsal horn of spinal cord, where glial cells accumulate and play a critical role in initiating allodynia (increased pain in response to light-touch). However, how painful stimuli in the periphery engage glial reactivity in the spinal cord remains unclear. Here, we found that a hind paw inflammation induced by CFA produces robust morphological changes in spinal astrocytes and microglia compatible with the reactive phenotype. Strikingly, we discovered that a single intrathecal injection with venom peptides that inhibit calcium channels reversed all the glial pathological features of the peripheral inflammation. These effects were more apparent in rats treated with the Phα1β spider toxin (non-specific calcium channel antagonist) than ω-MVIIA cone snail toxin (selective N-type calcium channel antagonist). These data reveal for the first time a venom peptide acting on glial structural remodeling in vivo . We, therefore, suggest that calcium-dependent plasticity is an essential trigger for glial cells to initiate reactivity, which may represent a new target for the antinociceptive effects of Phα1β and ω-MVIIA toxins in inflammatory pain conditions.

Peripheral biomarker and post-mortem brains studies have shown alterations of neuronal calcium sensor 1 (Ncs-1) expression in people with bipolar disorder or schizophrenia. However, its engagement by psychiatric medications and potential contribution to behavioral regulation remains elusive. We investigated the effect on Ncs-1 expression of valproic acid (VPA), a mood stabilizer used for the management of bipolar disorder. Treatment with VPA induced Ncs-1 gene expression in cell line while chronic administration of this drug to mice increased both Ncs-1 protein and mRNA levels in the mouse frontal cortex. Inhibition of histone deacetylases (HDACs), a known biochemical effect of VPA, did not alter the expression of Ncs-1. In contrast, pharmacological inhibition or genetic downregulation of glycogen synthase kinase 3β (Gsk3β) increased Ncs-1 expression, whereas overexpression of a constitutively active Gsk3β had the opposite effect. Moreover, adeno-associated virus-mediated Ncs-1 overexpression in mouse frontal cortex caused responses similar to those elicited by VPA or lithium in tests evaluating social and mood-related behaviors. These findings indicate that VPA increases frontal cortex Ncs-1 gene expression as a result of Gsk3 inhibition. Furthermore, behavioral changes induced by Ncs-1 overexpression support a contribution of this mechanism in the regulation of behavior by VPA and potentially other psychoactive medications inhibiting Gsk3 activity.The neuronal calcium sensor 1 (Ncs-1) is a Ca 2+ -binding protein that regulates neurotransmitter release 1 , dopamine D2 receptor (D2R) desensitization 2 and neuronal survival 3 , among other functions 4,5 . Alterations in Ncs-1 levels may contribute to psychiatric disorders. Indeed, the expression pattern of Ncs-1 is altered in schizophrenia and bipolar disorder patients 6,7 . In addition, inducible overexpression of Ncs-1 in the brain of rodents enhances exploration and spatial memory acquisition, and increases axonal sprouting 8,9 , whereas loss of Ncs-1 in knockout (KO) mice caused depressive-like, anxiety-like and impaired motivated behaviors 10,11 .Although evidence suggests that Ncs-1 is affected in schizophrenia and bipolar disorder, the effect of psychiatric medications on Ncs-1 remains unexplored. We investigated whether the mood-stabilizing drug valproate (VPA) could contribute to the regulation of brain Ncs-1. VPA is a first-line treatment for depressive and manic phases of bipolar disorder 12 . It alters gene expression and promotes neuroplasticity changes, which in recent years has been suggested to underlie malfunctioning of the neurocircuits related to the psychiatric symptoms [13][14][15] . Inhibition of histone deacetylases (HDACs) and glycogen synthase kinase 3 (Gsk3α and β) are the most prominent mechanisms suspected to be involved in the mood-stabilizing effects of VPA [16][17][18][19] .VPA has been demonstrated to be an inhibitor of HDACs both in vitro and in vivo 20,21 . Chromatin remodeling mediated through HDAC inhibition may lead to transcri...

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