About

Christoph Kellendonk, PhD, is a Professor of Molecular Pharmacology and Therapeutics in the Department of Psychiatry at Columbia University. He 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. Following his doctoral studies, he joined Eric Kandel's laboratory at Columbia University as a post-doctoral research fellow, where he developed an interest in using mouse genetics to study neuropsychiatric disorders. Since 2008, Dr. Kellendonk has been an independent investigator at Columbia University, focusing on understanding the biological underpinnings of psychiatric conditions, particularly schizophrenia. His laboratory employs circuit dissection tools in mice to investigate the neural circuits involved in cognitive, negative, and positive symptoms of schizophrenia, manipulating dopamine D2 receptor expression and neuronal activity in genetically defined sub-circuits of the striatum, as well as studying thalamo-prefrontal circuits in cognition and working memory. His research also explores the role of dopamine in generating false percepts related to auditory hallucinations, contributing to the understanding of neurobiological mechanisms underlying psychiatric disorders.

Research topics

• Neuroscience
• Computer Science
• Biology
• Chemistry
• Genetics
• Psychology
• Cell biology
• Medicine
• Internal medicine

Selected publications

• Altered striatal dopamine regulation in <i>ADGRL3</i> knockout mice

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-08-01

  preprintOpen access

  Abstract Dopaminergic signaling is essential for regulating movement, learning, and reward. Disruptions in this system are linked to neuropsychiatric disorders such as ADHD. ADGRL3, an adhesion G protein-coupled receptor highly expressed in the brain, is genetically associated with increased ADHD risk. ADGRL3 knockout in animals alters expression of dopaminergic markers and induces dopamine-related behavioral changes. However, its precise role in modulating dopamine signaling remains unclear. We investigated how ADGRL3 knockout affects striatal dopamine release in mice using ex vivo fast-scan cyclic voltammetry and in vivo fiber photometry with a dopamine sensor. Ex vivo measurements showed increased electrically-evoked dopamine release across the striatum. Conversely, in vivo recordings revealed reduced task-induced dopamine signals in the nucleus accumbens during an operant fixed interval task. This reduction was not due to impaired dopamine availability, as amphetamine-evoked release was unchanged. These findings suggest ADGRL3 modulates dopamine release in complex ways via different pre- and postsynaptic mechanisms.

  PublisherOA PDFDOI

• Translational Evidence for Dopaminergic Alteration of Basal Ganglia Functional Connectivity in Persons with Schizophrenia

  medRxiv · 2025-04-01

  preprintOpen access

  Importance: In prior work, a transgenic mouse model of the striatal dopamine dysfunction observed in persons with schizophrenia (PSZ) exhibited dopamine-related neuroplasticity in the basal ganglia. This phenotype has never been demonstrated in human PSZ. Objective: To identify a specific dopamine-related alteration of basal ganglia connectivity via task-based and resting-state functional magnetic resonance imaging (fMRI), neuromelanin-sensitive MRI (NM-MRI), and positron emission tomography (PET), in unmedicated PSZ. Design: This case-control study of unmedicated PSZ and healthy controls (HC) occurred between November 2014 and June 2018, with analyses performed between April 2023 and February 2025. Setting: C]-(+)-PHNO PET was collected at Yale University. Participants: Participants were aged 18-55, and demographically matched. PSZ were antipsychotic drug-naïve or drug-free for at least three weeks prior to recruitment. Main Outcomes and Measures: C]-(+)-PHNO binding potential in DCa. Results: =0.020). Conclusions and Relevance: This study provides in-vivo evidence of a dopamine-associated neural abnormality of DCa and GPe connectivity in unmedicated PSZ. This phenotype suggests a potential neurodevelopmental mechanism of working memory deficits in schizophrenia, representing a critical step towards developing treatments for cognitive deficits.

  PublisherDOI

• Remember Me? Adolescent Thalamic Inhibition Leads to Deficits in Cortical Maturation and Social Memory

  Biological Psychiatry Global Open Science · 2025-05-30

  articleOpen accessSenior authorCorresponding
  PublisherDOI

• Complementary roles of dorsal and ventral hippocampus in the flexible adaptation of goal-directed behavior

  Science Advances · 2025-11-28

  articleOpen access

  The ability to adapt previously learned behaviors is crucial for survival in dynamically changing environments. The hippocampus has been implicated in associative learning, but how hippocampus activity along its septotemporal axis contributes to flexible adaptation is unknown. Using in vivo Ca 2+ recordings and functional inhibition of dorsal CA1 (dCA1) and ventral CA1 (vCA1) neurons in mice during complementary cognitive flexibility tasks, we find that dCA1 is engaged and functionally required during consolidation of a learned contingency both before and after a rule change, whereas vCA1 is uniquely recruited during, and necessary for, early adaptation to a new contingency. This vCA1-dependent adaptation relies on a perseverative error signal, which is encoded in vCA1 and required for behavior updating. These results highlight a previously unknown division of labor within the hippocampus, in which vCA1 enables flexible adaptation when mismatches in expected and actual outcomes are detected, whereas dCA1 stabilizes newly learned information.

  PublisherDOI

• An ace in the hole? Opportunities and limits of using mice to understand schizophrenia neurobiology

  Molecular Psychiatry · 2025-05-22 · 2 citations

  reviewOpen accessSenior author
  PublisherOA PDFDOI

• A corticostriatal learning mechanism linking excess striatal dopamine and auditory hallucinations

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-03-18 · 1 citations

  preprintOpen access

  Auditory hallucinations are linked to elevated striatal dopamine, but their underlying computational mechanisms have been obscured by regional heterogeneity in striatal dopamine signaling. To address this, we developed a normative circuit model in which corticostriatal plasticity in the ventral striatum is modulated by reward prediction errors to drive reinforcement learning while that in the sensory-dorsal striatum is modulated by sensory prediction errors derived from internal belief to drive self-supervised learning. We then validate the key predictions of this model using dopamine recordings across striatal regions in mice, as well as human behavior in a hybrid learning task. Finally, we find that changes in learning resulting from optogenetic stimulation of the sensory striatum in mice and individual variability in hallucination proneness in humans are best explained by selectively enhancing dopamine levels in the model sensory striatum. These findings identify plasticity mechanisms underlying biased learning of sensory expectations as a biologically plausible link between excess dopamine and hallucinations.

  PublisherOA PDFDOI

• Inhibition of striatal indirect pathway during second postnatal week leads to long lasting deficits in motivated behavior

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-03-31

  preprintOpen accessSenior authorCorresponding

  Abstract Schizophrenia is a neuropsychiatric disorder with postulated neurodevelopmental etiology. Genetic and imaging studies have shown enhanced dopamine and D2 receptor occupancy in the striatum of patients with schizophrenia. However, whether alterations in postnatal striatal dopamine can lead to long lasting changes in brain function and behavior is still unclear. Here, we approximated striatal D2R hyperfunction in mice via designer receptor mediated activation of inhibitory Gi-protein signaling during a defined postnatal time window. We found that Gi-mediated inhibition of the indirect pathway during postnatal day 8-15 led to long lasting decreases in locomotor activity and motivated behavior measured in the adult animal. In vivo photometry further showed that the motivational deficit was associated with an attenuated adaptation of cue-evoked dopamine levels to changes in effort requirements. These data establish a sensitive time window of D2R-regulated striatal development with long lasting impacts on neuronal function and behavior.

  PublisherOA PDFDOI

• mPFC spike data Bolkan et al. 2027 Nat Neuro

  Figshare · 2024-01-01

  datasetOpen access1st authorCorresponding

  mPFC single unit data fro Bolkan et al. 2017 Nature Neuroscience. Explanation document to follow.

  PublisherDOI

• Prefrontal representations of retrospective spatial working memory in a rodent radial maze task

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-10-12 · 1 citations

  preprintOpen accessSenior authorCorresponding

  Abstract Working memory is the cognitive capacity for temporarily holding information in mind for processing or use. It has been theorized to depend upon executive and mnemonic subcomponents, although the contextual mapping of these subcomponents is not complete. Perturbations of prefrontal cortex (PFC) delay activity disrupt spatial working memory performance in rodent tasks. However, recordings of unperturbed PFC delay activity do not consistently contain mnemonic representations of spatial information in these tasks, calling into question the role that mnemonic PFC representations play in freely-moving spatial working memory. We hypothesized that increasing task complexity might increase the likelihood of mnemonic PFC representation emergence. We therefore used an automated eight-arm radial maze to implement a novel match-to-sample rodent spatial working memory task with seven options on each trial, and recorded calcium activity in PFC neurons during task performance. We found that the delay-phase activity of PFC neurons indeed contained mnemonic representations of spatial information at the population level. These representations were retrospective rather than prospective, and—surprisingly—were more evident on error trials. Together with previous results, these observations suggest that in freely-moving spatial working memory tasks, PFC mnemonic representations emerge to empower deviation from a routine behavioral strategy. Significance Statement Prefrontal cortex (PFC) activity is necessary for optimal performance of freely-moving spatial working memory tasks in rodents. Despite this, PFC representations of retrospective actions or stimuli—one quintessential working memory hallmark—are only variably observed during task delays, complicating our understanding of the PFC’s role in spatial working memory. Here, we examine cellular-resolution PFC activity in a high-optionality match-to-sample radial maze task and find retrospective delay representations. Strikingly, these delay representations are more evident in error trials. This suggests that in the freely-moving context, explicit PFC representations of retrospective information support deviations from an entrained behavioral strategy, rather than equally supporting all spatial working memory-based behavior.

  PublisherOA PDFDOI

• Adolescent Thalamoprefrontal Inhibition Leads to Changes in Intrinsic Prefrontal Network Connectivity

  eNeuro · 2024-08-01 · 7 citations

  articleOpen access

  Adolescent inhibition of thalamocortical projections from postnatal days P20 to 50 leads to long-lasting deficits in prefrontal cortex function and cognition in the adult mouse. While this suggests a role of thalamic activity in prefrontal cortex maturation, it is unclear how inhibition of these projections affects prefrontal circuitry during adolescence. Here, we used chemogenetic tools to inhibit thalamoprefrontal projections in male/female mice from P20 to P35 and measured synaptic inputs to prefrontal pyramidal neurons by layer (either II/III or V/VI) and projection target (mediodorsal thalamus (MD), nucleus accumbens (NAc), or callosal prefrontal projections) 24 h later using slice physiology. We found a decrease in the frequency of excitatory and inhibitory currents in layer II/III NAc and layer V/VI MD-projecting neurons while layer V/VI NAc-projecting neurons showed an increase in the amplitude of excitatory and inhibitory currents. Regarding cortical projections, the frequency of inhibitory but not excitatory currents was enhanced in contralateral mPFC-projecting neurons. Notably, despite these complex changes in individual levels of excitation and inhibition, the overall balance between excitation and inhibition in each cell was only altered in the contralateral mPFC projections. This finding suggests homeostatic regulation occurs within subcortically but not intracortical callosal-projecting neurons. Increased inhibition of intraprefrontal connectivity may therefore be particularly important for prefrontal cortex circuit maturation. Finally, we observed cognitive deficits in the adult mouse using this narrowed window of thalamocortical inhibition.

  PublisherOA PDFDOI

Recent grants

• Training in Schizophrenia andP sychotic Disorders: From Animal Models to Patients

  NIH · $11.6M · 1988–2026

• Thalamo-Prefrontal interactions in cognition: cortical layers

  NIH · $428k · 2018–2021

• An adolescent sensitive period for thalamo-prefrontal circuit maturation

  NIH · $446k · 2019–2022

• The role of thalamic dopamine D2 receptors in cocaine intake

  NIH · $413k · 2017–2020

• Functionally selective D2Rs, striatal circuit function and motivation

  NIH · $5.0M · 2011–2022

Frequent coauthors

• Sarah Canetta

  Columbia University Irving Medical Center

  117 shared

• François Tronche

  Centre National de la Recherche Scientifique

  94 shared

• Günther Schütz

  87 shared

• Peter D. Balsam

  Columbia University

  81 shared

• Holger M. Reichardt

  Universitätsmedizin Göttingen

  71 shared

• Eleanor H. Simpson

  New York State Psychiatric Institute

  66 shared

• Wolfgang Schmid

  63 shared

• Jonathan A. Javitch

  New York State Psychiatric Institute

  60 shared

Labs

• Abate-Shen LabPI