Abstract
Cortico-basal ganglia-thalamocortical loops are largely conceived as parallel circuits that process limbic, associative, and sensorimotor information separately. Whether and how these functionally distinct loops interact remains unclear. Combining genetic and viral approaches, we systemically mapped the limbic and motor cortico-basal ganglia-thalamocortical loops in rodents. Despite largely closed loops within each functional domain, we discovered a unidirectional influence of the limbic over the motor loop via ventral striatum-substantia nigra (SNr)-motor thalamus circuitry. Slice electrophysiology verifies that the projection from ventral striatum functionally inhibits nigro-thalamic SNr neurons. In vivo optogenetic stimulation of ventral or dorsolateral striatum to SNr pathway modulates activity in medial prefrontal cortex (mPFC) and motor cortex (M1), respectively. However, whereas the dorsolateral striatum-SNr pathway exerts little impact on mPFC, activation of the ventral striatum-SNr pathway effectively alters M1 activity. These results demonstrate an open cortico-basal ganglia loop whereby limbic information could modulate motor output through ventral striatum control of M1.
Highlights
To visualize the cortico-basal ganglia loops, we first mapped the input-output connections of the rodent striatum with the primary motor cortex (M1), secondary motor cortex (M2), and medial prefrontal cortex by injecting a mixture of cholera toxin b subunit (CTb, non-trans-synaptic, bidirectional tracer) and a retrogradely transported poly-synaptic, wild-type rabies virus (Wt-RABV) into each cortical area in rats. This strategy allowed us to compare the topography of the cortico-striatal input with that of striatal output neurons that multi-synaptically connect to the same area of cortex via the canonical basal ganglia direct pathway (Figure 1A)
Prior studies have established that 66–70 hr is adequate survival time for 3rd-order infection of Wt-RABV without 4th-order infection in rats (Aoki et al, 2019; Suzuki et al, 2012), so this procedure could determine tri-synaptic connections originating from striatum to cortex via the direct pathway (Kelly and Strick, 2004; Miyachi et al, 2006)
We dissected the topography of limbic and motor cortico-basal ganglia loops at each synaptic step and revealed a one-way influence of limbic loops onto motor loops
Summary
Cortico-basal ganglia circuits are crucial for emotional, cognitive, and sensorimotor functions in health and disease (Doya, 2000; Floresco, 2015; Gerdeman et al, 2003; Graybiel et al, 1994; Gunaydin and Kreitzer, 2016; Hikosaka et al, 2000; Jahanshahi et al, 2015; Jin and Costa, 2015; Marchand, 2010; Vaghi et al, 2017; Yin and Knowlton, 2006). The ‘limbic’ ventral striatum (VS), which receives limbic but not motor cortical input, alters behavioral output including locomotion activity, approach/avoidance behaviors, and recovery of skilled movement after spinal cord injury (Britt et al, 2012; Floresco, 2015; Saunders and Robinson, 2012; Sawada et al, 2015) These findings suggest that for a unified behavioral output, information across the different modalities must be integrated into motor circuits to drive action appropriately (Mogenson et al, 1980). Studies have largely focused on mapping monosynaptic inputs from cortex to the striatum (Hintiryan et al, 2016; Hooks et al, 2018; Voorn et al, 2004), emphasizing the topographic organization at the level of cortico-striatal projections To date, it is incompletely understood how these distinct ‘channels’ proceed through the rest of basal ganglia-thalamo-cortical circuitry and whether they interact at all. These results demonstrate an open cortico-basal ganglia-thalamocortical loop through which VS can modulate M1 activity, providing new insights into the limbic control over motor output in health and disease
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