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. 2014 Sep 15:8:163.
doi: 10.3389/fnsys.2014.00163. eCollection 2014.

The therapeutic potential of the cerebellum in schizophrenia

Affiliations

The therapeutic potential of the cerebellum in schizophrenia

Krystal L Parker et al. Front Syst Neurosci. .

Abstract

The cognitive role of the cerebellum is critically tied to its distributed connections throughout the brain. Accumulating evidence from anatomical, structural and functional imaging, and lesion studies advocate a cognitive network involving indirect connections between the cerebellum and non-motor areas in the prefrontal cortex. Cerebellar stimulation dynamically influences activity in several regions of the frontal cortex and effectively improves cognition in schizophrenia. In this manuscript, we summarize current literature on the cingulocerebellar circuit and we introduce a method to interrogate this circuit combining opotogenetics, neuropharmacology, and electrophysiology in awake-behaving animals while minimizing incidental stimulation of neighboring cerebellar nuclei. We propose the novel hypothesis that optogenetic cerebellar stimulation can restore aberrant frontal activity and rescue impaired cognition in schizophrenia. We focus on how a known cognitive region in the frontal cortex, the anterior cingulate, is influenced by the cerebellum. This circuit is of particular interest because it has been confirmed using tracing studies, neuroimaging reveals its role in cognitive tasks, it is conserved from rodents to humans, and diseases such as schizophrenia and autism appear in its aberrancy. Novel tract tracing results presented here provide support for how these two areas communicate. The primary pathway involves a disynaptic connection between the cerebellar dentate nuclei (DN) and the anterior cingulate cortex. Secondarily, the pathway from cerebellar fastigial nuclei (FN) to the ventral tegmental area, which supplies dopamine to the prefrontal cortex, may play a role as schizophrenia characteristically involves dopamine deficiencies. We hope that the hypothesis described here will inspire new therapeutic strategies targeting currently untreatable cognitive impairments in schizophrenia.

Keywords: anterior cingulate; cerebellum; cognitive symptoms; optogenetic stimulation; schizophrenia.

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Figures

Figure 1
Figure 1
During positron emissions tomography (PET) imaging of a task typically thought to be cerebellum dependent, eyeblink conditioning, hypofunction was revealed in the cingulocerebellar circuit. A double subtraction method where the baseline pseudoconditioning phase of unpaired tones and airpuffs was first subtracted and then the rCBF for patients with schizophrenia was subtracted from that of controls, show negative peaks indicating patients with schizophrenia have less rCBF than controls. This representative image shows hypofunction of the anterior cingulate (Talairach coordinates: −1, 30, 14) and cerebellar lobules IV/V, and IX (Talairach coordinates: −3, −67, −17) in patients with schizophrenia in comparison to healthy controls. For each illustration there are three orthogonal views per row with transaxial on the top, sagittal in the middle, and coronal on the bottom. Green crosshairs are used to show the location of the slice. Images follow radiological convention and show location as if facing the patient where the left side of the image represents the patient’s right side. The statistical maps of the PET, showing the regions where the two groups differed significantly at the 0.005 level, are superimposed on a composite magnetic resonance image (MRI) derived by averaging the MR scans from the subjects. Regions in red/yellow tones indicate positive peaks (greater activation in patients than in controls) and regions with blue/purple indicate negative peaks (less activity in patients than controls). The statistical results are portrayed using the value of the associated t-statistic, which is shown on the color bar on the right. The images are referred to as “t maps” showing all voxels in the image which exceed a display threshold.
Figure 2
Figure 2
Fronto-ponto-cerebellar tractography reconstructed on a 3D T1- weighted image (Kamali et al., 2010).
Figure 3
Figure 3
Proposed efferent cingulocerellar circuitry. (A) Schematic representation of the efferent cerebellar projections enabling cerebellar access to the medial prefrontal cortex/anterior cingulate via the ventrolateral thalamus and VTA. Two efferent pathways are thought to connect the cerebellum and prefrontal cortex (1) Cerebellar projections originating from dentate (DN) or fastigial nuclei (FN) to the contralateral thalamus and anterior cingulate cortex; and (2) Cerebellar projections originating from DN or FN to the contralateral ventral tegmental area (VTA) which send dopaminergic projections to the anterior cingulate cortex. The afferent pathways from the anterior cingulate back to the cerebellum via the pontine nuclei (PN) and inferior olive (IO). (B) Our tract tracing data following anterograde tracer (green) in the right dentate nuclei and retrograde tracer (red) in the contralateral (left) medial prefrontal cortex revealed tracer colocalization of both red and green beads on a single contralateral ventrolateral thalamic (VLTh) neuron (B).
Figure 4
Figure 4
Schematic representation of the cingulocerebellar pathways allowing the cerebellum access to the prefrontal cortex. We propose using optogenetic stimulation of cerebellar projection neurons in the thalamus to recover activity in aberrant prefrontal neuronal ensembles in schizophrenia. Channelrhodopsin, a light-activated channel, can be infused into cerebellar neurons rendering cerebellar projections photoexcitable. Stimulating thalamic (or VTA) optical fibers can selectively stimulate the cerebellar neuronal projections to the anterior cingulate while not affecting other cerebellar neuronal populations. This optogenetic paradigm can be used in animals exhibiting phenotypes of schizophrenia and other neuropsychiatric illnesses in combination with elementary cognitive tasks impaired in schizophrenia to recover cognitive function and probe the cingluocerebellar circuit.

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