Wireless Optogenetic Manipulation of Direct-Pathway Neurons of Basal Ganglia in Free Moving Mice

Abstract

Striatum is one of the major components of basal ganglia. More than 90% of principle neurons in striatum are medium spiny neuron (MSN). The MSNs are further subdivided into the direct-pathway (striatonigral or D1) MSNs or the indirect-pathway (striatopallidal or D2) MSNs. The striatonigral MSNs project to GPi and substantia nigra (SN). The striatopallidal MSNs project to globus pallidus externa (GPe), which can indirectly influence the SN via the subthalamic nuclei (STN). Disruption of two pathway have been implicated in the pathogenesis of neuropsychiatric disorders such as Parkinson's disease, Huntington's disease, Drug addiction and Schizophrenia. The development of optogenetics has introduced an elegant method to stimulate MSNs and basal ganglia circuits, both in vitro and in vivo. However, current optogenetics setup employs cumbersome tethers and commutators that prohibits the studying the free, natural behavior of the animal. Using a light weight (1-2 g) wireless infrared receiver coupled to optic fiber implants, we could deliver mW order light in free mouse. Injection of Cre-dependent Channelrhodopsin or/and halorhodops in an inverted open-reading-frame in Bacterial Artificial Chromosome (BAC) transgenic Drd1a-Cre mice enables us to precisely stimulate or/and inhibit genetically defined direct-pathway neurons. We have successfully employed such optogenetic device to examine more complex behavior in plus maze (for anxiety), three chamber interaction test (for social interaction) and rotarod tests. Our results revealed that direct-pathway stimulation elicits robust grooming behavior in free moving mice in their home cage, recapitulating the D1 receptor agonist-induced behavioral phenotypes in mice. These experiments demonstrate that the wireless optogenetic device can be readily used in complex behavioral experiments. Such technology will accelerate progress in both basic neuroscience and translational technologies and have strong potential for broader use in biology and medicine.