Cerebellar Purkinje cell activity modulates aggressive behavior

Jackman, Skyler L.; Chen, Christopher H.; Offermann, Heather L; Drew, Iain R; Harrison, Bailey M; Bowman, Anna M; Flick, Katelyn M; Flaquer, Isabella; Regehr, Wade G.

doi:10.1101/2020.01.06.891127

Cited by 9 publications

(11 citation statements)

References 38 publications

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“…Further support for non-motor roles of CB stems from clinical translational studies, which have linked CB dysfunction with neurodevelopmental disorders, posttraumatic stress disorder, generalized anxiety disorder, addiction, and cognitive and emotional disturbances known as cerebellar cognitive affective syndrome 8,[10][11][12][13][14][15][16][17][18] . These findings are further corroborated by evidence from animal studies, which solidify a role for the CB in the processing of valence, reward, reward anticipation and omission [19][20][21][22][23] ; emotional learning and aggression [24][25][26][27][28][29][30][31] ; and motivation [32][33][34] .…”

Section: Introductionsupporting

confidence: 60%

Cerebellar Activation Bidirectionally Regulates Nucleus Accumbens Core and Medial Shell

D’Ambra

Jung

Ganesan

et al. 2020

Preprint

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Traditionally viewed as a motor control center, the cerebellum (CB) is now recognized as an integral part of a broad, long-range brain network that serves limbic functions and motivates behavior. This diverse CB functionality has been at least partly attributed to the multiplicity of its outputs. However, relatively little attention has been paid to CB connectivity with subcortical limbic structures, and nothing is known about how the CB connects to the nucleus accumbens (NAc), a complex striatal region with which the CB shares functionality in motivated behaviors. Here, we report findings from in vivo electrophysiological experiments that investigated the functional connectivity between CB and NAc. We found that electrical microstimulation of deep cerebellar nuclei (DCN) modulates NAc spiking activity. This modulation differed in terms of directionality (excitatory vs. inhibitory) and temporal characteristics, in a manner that depends on NAc subregions: in the medial shell of NAc (NAcMed), slow inhibitory responses prevailed over excitatory ones, whereas the proportion of fast excitatory responses was greater in the NAc core (NAcCore) compared to NAcMed. Slow inhibitory modulation of NAcCore was also observed but it required stronger CB inputs compared to NAcMed. Finally, we observed shorter onset latencies for excitatory responses in NAcCore than in NAcMed, which argues for differential connectivity. If different pathways provide signal to each subregion, the divergence likely occurs downstream of the CB because we did not find any response-type clustering within DCN. Because there are no direct monosynaptic connections between CB and NAc, we performed viral tracing experiments to chart disynaptic pathways that could potentially mediate the newly discovered CB-NAc communication. We identified two anatomical pathways that recruit the ventral tegmental area and intralaminar thalamus as nodes. These pathways and the functional connectivity they support could underlie CB’s role in motivated behaviors.

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Section: Introductionsupporting

confidence: 60%

Cerebellar Activation Bidirectionally Regulates Nucleus Accumbens Core and Medial Shell

D’Ambra

Jung

Ganesan

et al. 2020

Preprint

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“…Prior evidence for a cerebellar role in organized cognition has come from lesions and correlational imaging studies ( 72 ). A wealth of recent murine studies has demonstrated a critical role for the cerebellum in multiple aspects of cognition ( 73 – 77 ). In this model we add social cognition to the growing list of cognitive domains dependent on cerebellar computation.…”

Section: Discussionmentioning

confidence: 99%

Cerebellar-Cortical Connectivity Is Linked to Social Cognition Trans-Diagnostically

et al. 2020

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Background: Psychotic disorders are characterized by impairment in social cognitive processing, which is associated with poorer community functioning. However, the neural mechanisms of social impairment in psychosis remain unclear. Social impairment is a hallmark of other psychiatric illnesses as well, including autism spectrum disorders (ASD), and the nature and degree of social cognitive impairments across psychotic disorders and ASD are similar, suggesting that mechanisms that are known to underpin social impairments in ASD may also play a role in the impairments seen in psychosis. Specifically, in both humans and animal models of ASD, a cerebellar–parietal network has been identified that is directly related to social cognition and social functioning. In this study we examined social cognition and resting-state brain connectivity in people with psychosis and in neurotypical adults. We hypothesized that social cognition would be most strongly associated with cerebellar–parietal connectivity, even when using a whole-brain data driven approach. Methods: We examined associations between brain connectivity and social cognition in a trans-diagnostic sample of people with psychosis ( n = 81) and neurotypical controls ( n = 45). Social cognition was assessed using the social cognition domain score of the MATRICS Consensus Cognitive Battery. We used a multivariate pattern analysis to correlate social cognition with resting-state functional connectivity at the individual voxel level. Results: This approach identified a circuit between right cerebellar Crus I, II and left parietal cortex as the strongest correlate of social cognitive performance. This connectivity-cognition result was observed in both people with psychotic disorders and in neurotypical adults. Conclusions: Using a data-driven whole brain approach we identified a cerebellar–parietal circuit that was robustly associated with social cognitive ability, consistent with findings from people with ASD and animal models. These findings suggest that this circuit may be marker of social cognitive impairment trans-diagnostically and support cerebellar–parietal connectivity as a potential therapeutic target for enhancing social cognition.

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“…In the last few years, several studies have further underscored the importance of the cerebellum in higher order function using acute, optogenetic manipulations of specific cell types. Acute activation of the cerebellar cortex disrupts hippocampal function and impairs performance in a spatial memory task [89], optogenetic activation and inhibition of Purkinje cells result in a reduction or increase in aggressive behaviors, respectively [90], and activation or inhibition of cerebellar fastigial nucleus neurons projecting to the periaqueductal gray modulate fear memories [91] (shown in Fig. 2).…”

Section: Disruptions In Cerebellar Function Lead To Social and Cognitive Deficits In Micementioning

confidence: 99%

Abnormal Cerebellar Development in Autism Spectrum Disorders

2021

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Autism spectrum disorders (ASD) comprise a group of heterogeneous neurodevelopmental conditions characterized by impaired social interactions and repetitive behaviors with symptom onset in early infancy. The genetic risks for ASD have long been appreciated: concordance of ASD diagnosis may be as high as 90% for monozygotic twins and 30% for dizygotic twins, and hundreds of mutations in single genes have been associated with ASD. Nevertheless, only 5–30% of ASD cases can be explained by a known genetic cause, suggesting that genetics is not the only factor at play. More recently, several studies reported that up to 40% of infants with cerebellar hemorrhages and lesions are diagnosed with ASD. These hemorrhages are overrepresented in severely premature infants, who are born during a period of highly dynamic cerebellar development that encompasses an approximately 5-fold size expansion, an increase in structural complexity, and remarkable rearrangements of local neural circuits. The incidence of ASD-causing cerebellar hemorrhages during this window supports the hypothesis that abnormal cerebellar development may be a primary risk factor for ASD. However, the links between developmental deficits in the cerebellum and the neurological dysfunctions underlying ASD are not completely understood. Here, we discuss key processes in cerebellar development, what happens to the cerebellar circuit when development is interrupted, and how impaired cerebellar function leads to social and cognitive impairments. We explore a central question: Is cerebellar development important for the generation of the social and cognitive brain or is the cerebellum part of the social and cognitive brain itself?

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Cerebellar Purkinje cell activity modulates aggressive behavior

Cited by 9 publications

References 38 publications

Cerebellar Activation Bidirectionally Regulates Nucleus Accumbens Core and Medial Shell

Cerebellar Activation Bidirectionally Regulates Nucleus Accumbens Core and Medial Shell

Cerebellar-Cortical Connectivity Is Linked to Social Cognition Trans-Diagnostically

Abnormal Cerebellar Development in Autism Spectrum Disorders

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