Christoph Kellendonk, PhD
Assistant Professor of Pharmacology (in Psychiatry)
Dr. Kellendonk obtained his PhD in the laboratory of Günther Schütz at the German Cancer Research Center in Heidelberg where he studied the function of the glucocorticoid receptor. He then joined Eric Kandel's laboratory at Columbia University in New York as a post doctoral research fellow where he became interested in genetic mouse models of neuropsychiatric disorders. Since 2008 Dr. Kellendonk is an Assistant Professor of Pharmacology in Psychiatry at Columbia University and the New York State Psychiatric Institute. His laboratory uses the mouse as an animal model to understand the molecular and physiological mechanisms that underlie cognitive and negative symptoms of schizophrenia.
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.