Cerebellar Stimulation Differentially Modulates Neuronal Activity in Mouse Prefrontal Cortex

Background:   There is no unique neuropathology associated with autism spectrum disorders (ASDs). However, the prefrontal cortex (PFC) and the cerebellum (CB) are two brain areas strongly implicated in ASD, suggesting that impaired cerebro-cerebellar communication may contribute to the development of ASD. Connections between the PFC and cerebellum have been found in primates (1) and Imaging studies suggest such connections also exist in humans (2). In mice electrical stimulation of the cerebellar dentate nucleus results in dopamine release in the PFC (3) but little is known how CB activity affects neuronal activity in the PFC. 

Objectives: We investigated how electrical stimulation of the cerebellar cortex affects neuronal activity in frontal and prefrontal cortical areas in awake behaving mice.  

Methods:   We recorded local field potential (LPF) and single unit spike activity with up to five extracellular recording electrodes in the prelimbic, secondary motor and/or frontal association areas (Ant.-Post.: Bregma +2, Lat: 0.2 - 2.5 mm). Electrical stimulation (10 ms, 50 Hz, 100 µA, for 1.0 s) was applied with a bipolar electrode to the surface of the cerebellar hemisphere (Ant. Post.: -6.2, Lat.: 2 - 2.5 mm). 

Results:   At rest, the fluctuations of LFP activity were strongly correlated between recording sites and showed large, synchronized amplitude negative peaks at irregular intervals, which were associated with pauses in single unit spike activity across multiple recording sites. Cerebellar stimulation eliminated negative LFP peaks for a period of a few to tens of seconds, depending on stimulus amplitude. We analyzed the responses of 229 single units to cerebellar cortical stimulation. Firing rate increased in 73 (31.9%) and decreased in 28 (12.2%) units with 128 units (55.9%) showing no change in firing rate following cerebellar stimulation. Unilateral cerebellar stimulation affected PFC neuronal activity bilaterally. 

Conclusions:  Our findings show that increasing cerebellar cortical activity via electrical stimulation differentially modulates LFP and spiking activity in awake mouse PFC neurons, resulting in a temporary desynchronization of PFC network activity, an effect that might involve dopamine transmission (3).

References:

1. Middleton, Strick, J Neurosci 21, 700 (2001).

2. Krienen, Buckner, Cerebral Cortex 19, 2485 (2009).

3. Mittleman, et al. Synapse 62, 544 (2008).