Regulation of parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry

Abstract

Neural circuits of the basal ganglia are critical for motor planning and action selection1-3. Two parallel basal ganglia pathways have been described4, which are proposed to exert opposing influences on motor function5-7. According to this classical model, activation of the direct pathway facilitates movement and activation of the indirect pathway inhibits movement. However, more recent anatomical and functional evidence has called into question the validity of this hypothesis8-10. Because this model has never been empirically tested, the specific function of these circuits in behaving animals remains unknown. Here, we directly activated basal ganglia circuitry in vivo, using optogenetic control11-14 of direct- and indirect-pathway medium spiny projection neurons (MSNs), achieved through Cre-dependent viral expression of channelrhodopsin-2 in the striatum of D1-Cre and D2-Cre BAC transgenic mice. Bilateral excitation of indirect-pathway MSNs elicited a parkinsonian state, distinguished by increased freezing, bradykinesia, and decreased locomotor initiations. In contrast, activation of direct-pathway MSNs reduced freezing and increased locomotion. In a mouse model of Parkinson's disease, direct pathway activation completely rescued deficits in freezing, bradykinesia, and locomotor initiation. Taken together, our findings establish a critical role for basal ganglia circuitry in the bidirectional regulation of motor behavior and indicate that modulation of direct pathway circuitry may represent an effective therapeutic strategy for ameliorating parkinsonian motor deficits.

P4‐253: Hilar GABAergic interneuron activity controls spatial learning and memory retrieval

“…The number of cFos-positive dentate granule neurons, which reflects neuronal activation [15,19], was also significantly higher on the illuminated side of the dentate gyrus compared to the contralateral, non-illuminated dentate gyrus (P,0.05) (Figs. 3A-C).…”

“…Slices were subsequently transferred to a holding chamber containing artificial cerebrospinal fluid (ACSF) containing (in mM) 125 NaCl, 26 NaHCO 3 , 1.25 NaH 2 PO 4 .H 2 O, 2.5 KCl, 1 MgCl, 2 CaCl, and 12.5 glucose at 33uC for 30 min. After resting for 1-5 h at room temperature, experiments were performed on slices perfused with ACSF, warmed to 31-33uC [15].…”

“…In vivo dentate gyrus recordings (Fig. 2D) were performed with an optrode (a linear, 16-site silicon electrode array with an integrated laser-coupled optical fiber) that elicited lightinduced neuronal activity changes up to 800 mm from the fiber tip [15]. Searching for neurons that responded to yellow laser illumination (1 mW at fiber tip), we identified seven with increased firing during the laser pulse, with an average change from 1.260.4 to 3.561.2 Hz (P,0.05) (Figs.…”

Optogenetics in neuroscience: what we gain from studies in mammals

“…They found that photoactivation of the indirect pathway results in a Parkinsonian state while optical stimulation of the direct pathway totally reverses the appearance of PD, a possible strategy for treatment [32] . Since dopamine (DA) deficiency is responsible for PD, attempts to control DA release were made in 2010.…”

“…Although optogenetics is applied to control the activity of targeted neurons or to investigate neuronal circuits in the brain, its value in the treatment of diseases due to neuronal degeneration also cannot be ignored, since initial efforts have paid off [32,80] . These promising methods provide new directions to reverse neuronal degeneration.…”