Homologous organization of cerebellar pathways to sensory, motor, and associative forebrain

Abstract

16Cerebellar outputs take multisynaptic paths to reach higher brain areas, impeding tracing 17 efforts. Here we quantify pathways between cerebellum and contralateral 18 thalamic/corticostriatal structures using the anterograde transsynaptic tracer herpes 19 simplex virus type 1 (H129), the retrograde tracer pseudorabies virus (Bartha), adeno-20 associated virus, and a whole-brain pipeline for neuron-level analysis using light-sheet 21 microscopy. In ascending pathways, sensorimotor regions contained the most labeled 22 neurons, but higher densities were found in associative areas, including orbital, anterior 23 cingulate, prelimbic, and infralimbic cortex. Ascending paths passed through most 24 thalamic nuclei, especially ventral posteromedial and lateral posterior (sensorimotor), 25 mediodorsal (associative), and reticular (modulatory) nuclei. Retrograde tracing revealed 26 descending paths originating largely from somatomotor cortex. Patterns of ascending 27 influence correlated with anatomical pathway strengths, as measured by brainwide 28 mapping of c-Fos responses to optogenetic inhibition of Purkinje cells. Our results 29 reveal parallel functional networks linking cerebellum to forebrain and suggest that 30 cerebellum uses sensory-motor information to guide both movement and nonmotor 31 functions. 32 most mammalian brains 8 . The major descending corticocerebellar pathway passes through the 41 pons and the majority of returning ascending fibers pass through the thalamus 9,10 , comprising 42 two massive within-brain long-distance pathways 11 . Other polysynaptic pathways exist between 43 the cerebellum and neocortex, including a smaller ascending pathway through ventral tegmental 44 area that has attracted recent interest 12 . These descending and ascending pathways are 45 suggested to form closed loops 13 , giving each cerebellar region one or more specific neocortical 46 partners with which it exchanges information. 47This picture lacks critical information: the identity of those distant regions, which have 48 been difficult to map. Given the brain-wide nature of cerebello-cortical pathways, researchers 49 have used large-scale approaches to examine the functional significance of these pathways. 50Transcranial magnetic stimulation in humans demonstrated that the cerebellum influences 51 neocortical excitability 14 , including cognitive and affective circuits 15 . Functional MRI can attain 52 subcentimeter resolution, detect long-distance correlations 16 , and when coupled with cerebellar 53 stimulation, demonstrate causal relationships 17 . Functional imaging at cellular resolution in 54 nonhuman animals has been made possible by visualizing c-Fos, an immediate-early gene 55 product whose expression is regulated by neural activity. Although useful in demonstrating 56 communication with distant brain regions, these methods do not provide cellular-resolution 57 information about cerebello-cortical circuits. 58Pathways entering and exiting the cerebellum pass through synapses in the brainstem 59 and the cer...

Cerebellum-Specific Deletion of the GABAA Receptor δ Subunit Leads to Sex-Specific Disruption of Behavior

“…In addition, hypoactivation of the PVN in cb δ KO mice can indicate hypothalamic–pituitary-adrenal (HPA) axis dysregulation and chronic stress in cb δ KO animals ( Cohen et al, 2006 ; Kinlein et al, 2015 ; Whitaker and Gilpin, 2015 ). These observations are in line with recent tracing studies ( Fujita et al, 2020 ; Hashimoto et al, 2018 ; Pisano et al, 2020 ) and suggest that altering sensory integration in the input layer can affect numerous circuits throughout the brain.…”

Allostasis as a core feature of hierarchical gradients in the human brain

“…In fact, recent work suggests that the predictive construction of interoceptive signals may be necessary for successful allostasis (Barrett, 2017;Gu & FitzGerald, 2014;Pezzulo et al, 2015). Second, the cortical limbic nodes in both networks, and their points of overlap, have extensive connectivity to subcortical and brainstem structures that are important for allostasis and interoception (Figure 1C) as well as to the cerebellum and the hippocampus, both of which have connections to the structures that process outgoing visceromotor and incoming interoceptive signals (Onat & Çavdar, 2003;Pisano et al, 2021;Suarez et al, 2018;Vertes, 2015). Third, the allostaticinteroceptive system contains portions of motor and pre-motor cortices, consistent with tracttracing evidence that primary motor cortex contains visceromotor maps (Levinthal & Strick, 2012, 2020; this is also consistent with evidence that the anterior mid-cingulate cortex is considered a pre-motor area in the literature on skeletomotor control, and it may be a hub for visceromotor and skeletomotor integration (reviewed in Touroutoglou et al, 2020).…”

Ablation of STAT3 in Purkinje cells reorganizes cerebellar synaptic plasticity in long-term fear memory network

“…Although the conditioned response of PCs after fear conditioning has not been reported, the decreased output of PCs in STAT3 PKO mice may disinhibit the activity of deep cerebellar nuclei (DCN), and DCN may send neural signals to other fear-related regions ( Figure 7 ). Recently, it has been identified that the cerebellum has pathways to sensorimotor, associative, and modulatory forebrain ( Pisano et al, 2020 ). As previous studies showed, fear memory network is distributed in the forebrain ( Wager et al, 2015 ; Tovote et al, 2015 ).…”