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:10.7554/elife.53229

Cited by 41 publications

(24 citation statements)

References 52 publications

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“…Further support for non-motor CB roles 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] ; and motivation [31][32][33] .…”

Section: Introductionsupporting

confidence: 59%

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: 59%

Cerebellar Activation Bidirectionally Regulates Nucleus Accumbens Core and Medial Shell

D’Ambra

Jung

Ganesan

et al. 2020

Preprint

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“…It is also likely that in brain slice, spike frequency adaptation prevents DCN neurons from firing at high rates in the absence of PC inputs. Finally, spike frequency adaptation likely contributes to the observation that acutely increasing PC activity or decreasing DCN activity reduces aggression (Heath 1977, Cooper et al 1976, Reis et al 1973, Jackman et al 2020, Zanchelli and Zoccolini, 1954), whereas chronically removing PC inhibition by lesioning the cerebellar cortex, which would be predicted to increase DCN firing, similarly reduces aggression (Sprague and Chambers 1959, Berman 1997).…”

Section: Discussionmentioning

confidence: 99%

Unusually slow spike frequency adaptation in deep cerebellar nuclei neurons preserves linear transformations on the sub-second time scale

Khan

Chen

Regehr

2021

Preprint

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Purkinje cells (PCs) are spontaneously active neurons of the cerebellar cortex that inhibit glutamatergic projection neurons within the deep cerebellar nuclei (DCN) that in turn provide the primary cerebellar output. Brief reductions in PC firing rapidly increase DCN neuron firing. However, prolonged reductions in PC inhibition, as seen in some disease states, certain types of transgenic mice, and in acute slices of the cerebellum, do not evoke large sustained increases in DCN firing. Here we test whether there is a mechanism of spike-frequency adaptation in DCN neurons that could account for these properties. We find that prolonged optogenetic suppression of PC synapses in vivo transiently elevates PC firing that strongly adapts within ten seconds. We perform current-clamp recordings at near physiological temperature in acute brain slices to examine how DCN neurons respond to prolonged depolarizations. Adaptation in DCN neurons is exceptionally slow and bidirectional. A depolarizing current step evokes large initial increases in firing that decay to less than 20% of the initial increase within approximately ten seconds. Such slow adaptation could allow DCN neurons to adapt to prolonged changes in PC firing while maintaining their linear firing frequency-current relationship on subsecond time scales.

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“…role for the cerebellum in multiple aspects of cognition (73)(74)(75)(76)(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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Cerebellar Purkinje cell activity modulates aggressive behavior

Cited by 41 publications

References 52 publications

Cerebellar Activation Bidirectionally Regulates Nucleus Accumbens Core and Medial Shell

Cerebellar Activation Bidirectionally Regulates Nucleus Accumbens Core and Medial Shell

Unusually slow spike frequency adaptation in deep cerebellar nuclei neurons preserves linear transformations on the sub-second time scale

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

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