Departments And Divisions
- Department of Psychiatry
Division of Molecular Therapeutics
- Assistant Professor of Pharmacology (in Psychiatry)
Inhibition of Medio-Dorsal Thalamus Disrupts Thalamo-Frontal Connectivity and Cognition
Cognitive deficits are central to schizophrenia and understanding them is of particular significance as they are highly predictive for the long-term prognosis of the disease and are essentially resistant to treatment. While efforts in understanding the underlying mechanisms of cognitive symptoms have focused on the identification of abnormalities in specific brain structures, it has become increasingly clear that alterations in functional connectivity between distinct brain areas might account for these deficits. In this context, imaging studies performed in patients associated cognitive deficits with decreased activity in the medio-dorsal thalamus (MD) and reduced functional connectivity between the MD and the prefrontal cortex (PFC). Although these findings suggest a potential involvement for impaired thalamo-frontal communication in the generation of cognitive deficits, the causal relationship between both remains unclear.
To address this issue, we used a pharmacogenetic approach in mice to diminish MD neuron activity and assayed the behavioral and physiological consequences. We found that a subtle decrease in MD activity is sufficient to trigger selective impairments in cognitive flexibility and spatial working memory, two prefrontal dependent functions. In vivo recordings further revealed that during the spatial working memory task, MD-PFC beta-range (13-30Hz) synchrony increased during epochs of the task associated with peak mnemonic demand. Strikingly, this task-related increase was disrupted by reducing MD activity. Consistent with a role for thalamo-frontal circuit in working memory, MD-PFC beta-synchrony increased during task acquisition and decreasing MD activity delayed both learning of the task and the associated increase in beta-coherence. These data suggest that MD hypofunction can lead to cognitive impairment by disrupting thalamo-frontal functional connectivity. These findings further suggest that altered thalamo-frontal dysconnectivity could be involved in the generation of the cognitive symptoms of schizophrenia.
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- Neurobiology of Learning and Memory
- Models of Psychiatric Disorders
- Neurobiology of Disease
- Eduardo Gallo, PhD
- Fernanda Carvalho
- Jozsef Meszaros
- Lindsay Kenney
- Scott Bolkan
- Sarah Canetta, PhD
- Val Monrose, Lab Manager Kolb 3
- Abigail Clark
- Gallo EF, Salling MC, Feng B, Morón JA, Harrison NL, Javitch JA, Kellendonk C. (2015) Upregulation of dopamine D2 receptors in the nucleus accumbens indirect pathway increases locomotion but does notreduce alcohol consumption. Neuropsychopharmacology. 40:1609-1618. doi: 10.1038/npp.2015.11.
- Biezonski DK, Trifilieff P, Meszaros J, Javitch JA, Kellendonk C. (2015). Evidence for limited D1 and D2 receptor coexpression and colocalization within the dorsal striatum of the neonatal mouse. J Comp Neurol. 523:1175-1189. doi: 10.1002/cne.23730.
- Parnaudeau S, Taylor K, Bolkan SS, Ward RD, Balsam PD, Kellendonk C. (2015) Mediodorsal thalamus hypofunctionimpairs flexible goal-directed behavior. Biol Psychiatry. 77:445-453. doi: 10.1016/j.biopsych.
- Cazorla M, de Carvalho FD, Chohan MO, Shegda M, Chuhma N, Rayport S, Ahmari SE, Moore H, Kellendonk C. (2014) Dopamine D2 receptors regulate the anatomical and functional balance of basal ganglia circuitry. Neuron. 81:153-164. doi: 10.1016/j.neuron.
- Parnaudeau S, O'Neill PK, Bolkan SS, Ward RD, Abbas AI, Roth BL, Balsam PD, Gordon JA, Kellendonk C. (2013) Inhibition of mediodorsal thalamus disrupts thalamofrontal connectivity and cognition. Neuron. 77:1151-1162. doi: 10.1016/j.neuron.
- Cazorla M, Shegda M, Ramesh B, Harrison NL, Kellendonk C. (2012) Striatal D2 receptors regulate dendritic morphology of medium spiny neurons via Kir2 channels. J Neurosci. 32:2398-2409. doi: 10.1523/JNEUROSCI.6056-11.2012.
For a complete list of publications, please visit PubMed.gov