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Busch, S. E.

Publications and source records attributed to Busch, S. E..

5 recordsLinked to original sources

Cerebellar Purkinje cells change dendritic architecture during primate evolution

Vertebrate evolution has driven adaptive remodeling of brain regions impacted by changing sensorimotor demands. The cerebellum--a hindbrain area mediating associative learning and predictive coding--is thought to participate in diverse motor and non-motor behaviors across vertebrate species by duplicating and repurposing a conserved cortical circuit. Yet, few studies systematically compare circuit architecture across cerebellar evolution. We recently found that human Purkinje cells (PCs, the principal neuron of the cerebellar cortex) almost universally have multiple primary dendrites, a structural motif that confers distinct signaling properties, as shown by experiments in mice where this motif is present but less common. Seeking evolutionary insight, we developed a framework to parameterize and compare PC morphology across 11 simiiform (anthropoid) primates representing 40 million years of evolution, and mice as an outgroup. Dendritic architecture shifts profoundly from single primary dendrites with vertical orientation in mice and monkeys to multiple horizontally oriented primary dendrites in apes and, particularly pronounced, in humans. Increasing dendritic compartmentalization in the human lineage is produced by monotonic, stepwise, or human-specific trends across individual morphological traits. PC morphology is high-dimensional, with most features varying widely and independently, yet clade identity can be readily predicted from multivariate morphospace profiles. Phylogenetic patterns are not well explained by tissue foliation or allometric scaling, supporting the hypothesis that morphological variation is constrained by functional demands. Echoing a core principle of brain evolution that selection pressure drives fine-tuning of circuit elements rather than total circuit rearrangement, PC dendrite morphology may serve as a key node for cerebellar adaptation amid a conserved circuit architecture.

neuroscience↗

Non-allometric expansion and enhanced compartmentalization of Purkinje cell dendrites in the human cerebellum

Purkinje cell (PC) dendrites are optimized to integrate the vast cerebellar input array and drive the sole cortical output. PCs are classically seen as stereotypical computational units, yet mouse PCs are morphologically diverse and those with multi-branched structure can receive non-canonical climbing fiber (CF) multi-innervation that confers independent compartment-specific signaling. While otherwise uncharacterized, human PCs are universally multi-branched. Do they exceed allometry to achieve enhanced integrative capacities relative to mouse PCs? To answer this, we used several comparative histology techniques in adult human and mouse to analyze cellular morphology, parallel fiber (PF) and CF input arrangement, and regional PC demographics. Human PCs are substantially larger than previously described; they exceed allometric constraint by cortical thickness and are the largest neuron in the brain with 6-7cm total dendritic length. Unlike mouse, human PC dendrites ramify horizontally to form a multi-compartment motif that we show can receive multiple CFs. Human spines are denser (6.9 vs 4.9 spines/m), larger ([~]0.36 vs 0.29m), and include an unreported spine cluster structure--features that may be congruent with enhanced PF association and amplification as human-specific adaptations. By extrapolation, human PCs may receive 500,000 to 1 million synaptic inputs compared with 30-40,000 in mouse. Collectively, human PC morphology and input arrangement is quantitatively and qualitatively distinct from rodent. Multi-branched PCs are more prevalent in posterior and lateral cerebellum, co-varying with functional boundaries, supporting the hypothesis that this morphological motif permits expanded input multiplexing and may subserve task-dependent needs for input association.

neuroscience↗

Intrinsic and synaptic determinants of receptive field plasticity in Purkinje cells of the mouse cerebellum

Non-synaptic ( intrinsic) plasticity of membrane excitability contributes to aspects of memory formation, but it remains unclear whether it merely facilitates synaptic long-term potentiation or plays a permissive role in determining the impact of synaptic weight increase. We use tactile stimulation and electrical activation of parallel fibers to probe intrinsic and synaptic contributions to receptive field plasticity in awake mice during two-photon calcium imaging of cerebellar Purkinje cells. Repetitive activation of both stimuli induced response potentiation that is impaired in mice with selective deficits in either synaptic or intrinsic plasticity. Spatial analysis of calcium signals demonstrated that intrinsic, but not synaptic plasticity, enhances the spread of dendritic parallel fiber response potentiation. Simultaneous dendrite and axon initial segment recordings confirm these dendritic events affect axonal output. Our findings support the hypothesis that intrinsic plasticity provides an amplification mechanism that exerts a permissive control over the impact of long-term potentiation on neuronal responsiveness.

neuroscience↗

Multiple climbing fiber innervation of mature Purkinje cells with distinct dendritic subfields

Canonically, each Purkinje cell in the adult cerebellum receives only one climbing fiber from the inferior olive. Underlying current theories of cerebellar function is the notion that this highly conserved one-to-one relationship renders Purkinje dendrites into a single computational compartment. However, we show that multiple primary dendrites are a near-universal morphological feature in human. Using tract-tracing, immunolabeling, and in vitro electrophysiology, we demonstrate in mice that [~]25% of mature polydendritic cells receive more than one climbing fiber input. Two-photon calcium imaging in vivo reveals that separate dendrites can exhibit distinct response properties to sensory stimulation, indicating some polydendritic cells integrate functionally independent climbing fiber receptive fields. These findings reveal that Purkinje cells are morphologically and functionally more diverse than previously thought.

neuroscience↗

Intrinsic temporal tuning of neurons in the optic tectum is shaped by multisensory experience

Homeostatic intrinsic plasticity is often described as an adjustment of neuronal excitability to maintain stable spiking output. Here we report that intrinsic plasticity in the tectum of Xenopus tadpoles also supports temporal tuning, wherein neurons independently adjust spiking responses to fast and slow patterns of synaptic activation. Using the dynamic clamp technique, and five different types of visual, acoustic, and multisensory conditioning, we show that in tadpoles exposed to light flashes, tectal neurons became selective for fast synaptic inputs, while neurons exposed to looming and multisensory stimuli remained responsive to longer inputs. We also report a homeostatic co-tuning between synaptic and intrinsic temporal properties in tectal cells, as neurons that naturally received fast synaptic inputs tended to be most responsive to long-lasting synaptic conductances, and the other way around. These results expand our understanding of plasticity in the brain, and inform future work on the mechanisms of sensorimotor transformation. Significance statementWith the recent explosion of work in neural connectivity reconstruction and biologically inspired deep learning, most researchers concentrate on the topology of connections between neurons, rather than on differences in neuronal tuning. Here we show that in a sensory network in Xenopus tadpoles, different neurons are tuned, and respond stronger, to either short or long synaptic inputs. This tuning tended to be opposite to the actual dynamics of synaptic inputs each cell received, such that neurons that normally receive shorter inputs generated stronger spiking in response to longer testing currents, and the other way around. This observation shows that even in networks that dont generate oscillations, neurons reshape their temporal selectivity, to optimize their impact on distributed calculations.

neuroscience↗