Novel cerebello-amygdala connections provide missing link between cerebellum and limbic system

Abstract

The cerebellum is emerging as a powerful regulator of cognitive and affective processing and memory in both humans and animals and has been implicated in affective disorders. How the cerebellum supports affective function remains poorly understood. The short-latency (just a few ms) functional connections that were identified between the cerebellum and amygdala -a structure crucial for the processing of emotion and valence- more than 4 decades ago raise the exciting, yet untested, possibility that a cerebellum-amygdala pathway communicates information important for emotion. The major hurdle in rigorously testing this possibility is the lack of knowledge about the anatomy and functional connectivity of this pathway. Our initial anatomical tracing studies in mice excluded the existence of a direct monosynaptic pathway between cerebellum and amygdala. Using transsynaptic tracing techniques, we have identified a novel disynaptic pathway that connects the cerebellar output nuclei to the basolateral amygdala. This pathway recruits the understudied intralaminar thalamus as a node. Using ex vivo optophysiology and super-resolution microscopy, we provide the first evidence for the functionality of the pathway, thus offering a missing mechanistic link between the cerebellum and amygdala. This discovery provides a connectivity blueprint between the cerebellum and a key structure of the limbic system. As such, it is the requisite first step toward obtaining new knowledge about cerebellar function in emotion, thus fundamentally advancing understanding of the neurobiology of emotion, which is perturbed in mental and autism spectrum disorders.

The cerebellum and fear extinction: evidence from rodent and human studies

“…fully understood, a summary of its functional and structural connectivity with vital components of the limbic system have previously been highlighted by Apps and Strata (2015). The cerebellum is connected directly with the periaqueductal grey (Teune et al, 2000;Koutsikou et al, 2014;Frontera et al, 2020;Vaaga et al, 2020;Lawrenson et al, 2022), the ventral tegmental area (VTA; Watabe-Uchida et al, 2012;Carta et al, 2019;Pisano et al, 2021), the thalamus (Watabe- Uchida et al, 2012;Apps and Strata, 2015;Gornati et al, 2018;Pisano et al, 2021) and hypothalamus (Dietrichs and Haines, 1989;Apps and Strata, 2015) as well as indirectly with other cortical and subcortical structures such as the amygdala (Jung et al, 2022), the anterior cingulate cortex, hippocampus and the striatum (Moreno-Rius, 2018).…”

Cerebellar control of fear learning via the cerebellar nuclei–Multiple pathways, multiple mechanisms?

“…This allows the cerebellum to form a loop with other brain areas and to shape their output via recurrent loops (reviews: Person and Khodakhah, 2016;Tanaka et al, 2020). Cerebellar function has been extensively studied in motor function and learning but less in emotional learning, despite the existence of multiple anatomical connections between the cerebellum and structures in the limbic system and the known impact of cerebellar lesions on emotional behavior (Groenewegen, 1988;Schmahmann and Sherman, 1997;Sacchetti et al, 2002;Watson et al, 2009;Strata et al, 2011;Stoodley, 2012;Farley et al, 2016;Hintzen et al, 2018;Kostadinov et al, 2019;Frontera et al, 2020Frontera et al, , 2023Jung et al, 2022).…”

“…The cerebellum is anatomically connected through one or two synapses to many important structures in fear learning, e.g., it sends monosynaptic projections to the ventrolateral periaqueductal gray (Frontera et al, 2020) and to thalamic areas projecting to the basolateral amygdala (Jung et al, 2022) and prefrontal cortex (Groenewegen, 1988;Hintzen et al, 2018;Frontera et al, 2023), while the cerebellar cortex receives emotion-related input via the basilar pontine nucleus (Farley et al, 2016) and the inferior olive (Watson et al, 2009;Kostadinov et al, 2019). Still, evidence on the exact influence of the cerebellum has only emerged recently.…”

Cerebellar contribution to the regulation of defensive states

“…Inactivation of both during the recall session caused long-lasting amnesic effects, since rats did not recover the fear memory over time, not even after a reminder shock (Sacchetti et al, 2007). The advancement of neuroscientific methodologies recently allowed the demonstration of disynaptic connections between the DCN (FN and IN) and the BLA in mice, synapsing within the centromedial and parafascicular thalamic nuclei (Frontera et al, 2020;Jung et al, 2022). Due to the cerebellum's role in prediction error generation (Popa and Ebner, 2019) and the emotional valence information encoded by BLA (Janak and Tye, 2015), this pathway may be involved in encoding the information about the prediction and valence of a US.…”