Biology subjects

Dombeck, D. A.

Publications and source records attributed to Dombeck, D. A..

12 recordsLinked to original sources

bioRxiv2026

A red fluorescent sensor for intensity-and lifetime imaging of cAMP in living cells

cAMP (cyclic adenosine monophosphate) is a crucial intracellular messenger involved in neuromodulation and plasticity, but more information on its spatiotemporal regulation is desirable. Here we constructed a red fluorescent indicator based on a truncated cAMP binding site derived from a regulatory PKA subunit of protozoan origin. It contains a single binding site for cAMP highly specific for cAMP over cGMP. chILI (cAMP highly-responsive Intensity and Lifetime Indicator) can be imaged as an intensity-based probe, but alternatively also offers options for fluorescence lifetime imaging. When expressed in the mouse brain using AAV-vector mediated gene transfer, it reports spontaneous and evoked cAMP transients from CA1 neurons in the hippocampus of awake mice. chILI will add valuable options for monitoring cAMP in vitro and in vivo.

neuroscience↗

bioRxiv2025

Distinct neocortical and entorhinal networks for time, space, and reward

Variables relevant to behavior and cognition are often synthesized via computations that combine external cues and internal states. Especially salient and ubiquitous among these variables are time, space, and reward, but how they are represented throughout the neocortex and the entorhinal cortex is not well understood. Here, we utilized a behavioral task in virtual reality that includes timing, navigation, and reward components. Using a multifocus microscope that permits simultaneous mesoscopic Ca2+ imaging of neocortex and entorhinal cortex, we uncover dedicated and distinct subnetworks for interval timing, spatial navigation, and reward. Interestingly, the timing subnetwork demonstrated more prominent signaling in expert mice and features a strong contribution from barrel cortex that is not explained by ongoing whisking, pointing towards a role for this cortex in interval timing. Our results provide previously unknown details about the brainwide networks related to time, space, and reward and will allow for future interrogation of their interactions and computations.

neuroscience↗

bioRxiv2025

Hippocampal Fos-expressing neurons stably encode boundaries in novel environments

The hippocampus recruits place cell ensembles to represent novel environments, but how gene expression relates to this reorganization and its stabilization remains unclear. We imaged calcium transients and Fos-expression changes across ~30,000 CA1 neurons and found that neurons with higher Fos increases were more likely to be place cells in novel environments, rapidly cluster around environmental boundaries, and maintain stable boundary encoding across days, suggesting a role of Fos expression in place cell organization and stabilization.

neuroscience↗

bioRxiv2025

Distinct brain regions map olfactory and visual spaces

The hippocampus contains a multisensory cognitive map that incorporates spatial cues from across the senses, such as vision and olfaction. However, how primary sensory information transforms along pathways to the hippocampus into this single, combined map is largely unknown. Specifically, does the hippocampus generate or inherit the multisensory map of space? Here, we used multisensory virtual reality and large-scale functional imaging to determine if and how the main input regions to hippocampus, the lateral and medial entorhinal cortices (LEC and MEC, respectively), map olfactory and visual sensory spaces in navigating mice. We discovered that, in contrast to multisensory mapping in the hippocampus, LEC preferentially maps olfactory space while MEC preferentially maps visual space, regardless of the behavioral relevance of the spaces. This establishes the existence of largely independent brain maps for different sensory spaces, suggesting that the hippocampus builds the cognitive map by combining modality-specific maps from pre-synaptic cortical regions.

neuroscience↗

bioRxiv2025

Leucine-rich repeat kinase 2 impairs the release sites of Parkinson's disease vulnerable dopamine axons

The end-stage pathology of Parkinsons disease (PD) involves the loss of dopamine-producing neurons in the substantia nigra pars compacta (SNc). However, synaptic deregulation of these neurons begins much earlier. Understanding the mechanisms behind synaptic deficits is crucial for early therapeutic intervention, yet these remain largely unknown. In the SNc, different dopamine neuron subtypes show varying susceptibility patterns to PD, complicating our understanding. This study uses intersectional genetic mouse models to uncover synaptic perturbations in vulnerable dopamine neurons, focusing on the LRRK2 kinase, a protein closely linked to PD. Through a combination of immunofluorescence and advanced proximity labeling methods, we found higher LRRK2 expression in the most vulnerable dopamine neuron subclusters. High-resolution imaging revealed that pathogenic LRRK2 disrupts release sites in vulnerable dopamine axons, leading to decreased in vivo spontaneous and evoked striatal dopamine release in mice with LRRK2 mutations. Proteomic and biochemical analyses indicate that mutant LRRK2 increases the phosphorylation of RAB3 proteins, reducing their interactions with RIM1and RIM2 effector proteins and impacting their synaptic functions. Overall, this research highlights the cell-autonomous dysfunctions caused by mutant LRRK2 in neurons, which are primarily affected by the disease. It also provides a framework for future therapeutic strategies for early nigrostriatal synaptic deficits in PD.

neuroscience↗

bioRxiv2025

Hippocampal Representational Drift Persists in a Stable Multisensory Virtual Environment

Experiments tracking hippocampal place cells in mice navigating the same real environment have found significant changes in neural representations over days. However, there is currently a debate over whether such "representational drift" serves an intrinsic function, such as distinguishing similar experiences occurring at different times, or is instead observed due to subtle differences in the sensory environment or behavior. Here, we used the experimental control offered by a multisensory virtual reality (VR) system to determine that differences in sensory environment or behavior do not detectably change drift rate. We also found that the excitability of individual place cells was most predictive of their representational drift over subsequent days, with more excitable cells exhibiting less drift. These findings establish that representational drift occurs in mice even with highly reproducible environments and behavior and highlight neuronal excitability as a key factor of long-term representational stability.

neuroscience↗

bioRxiv2025

Navigating uncertainty: reward location variability induces reorganization of hippocampal spatial representations

Navigating uncertainty is crucial for survival, with the location and availability of reward varying in different and unsignalled ways. Hippocampal place cell populations over-represent salient locations in an animals environment, including those associated with rewards; however, how the spatial uncertainties impact the cognitive map is unclear. We report a virtual spatial navigation task designed to test the impact of different levels and types of uncertainty about reward on place cell populations. When the reward location changed on a trial-by-trial basis, inducing expected uncertainty, a greater proportion of place cells followed along, and the reward and the track end became anchors of a warped spatial metric. When the reward location then unexpectedly moved, the fraction of reward place cells that followed was greater when starting from a state of expected, compared to low, uncertainty. Overall, we show that different forms of potentially interacting uncertainty generate remapping in parallel, task-relevant, reference frames.

neuroscience↗

bioRxiv2024

Molecular and spatial transcriptomic classification of midbrain dopamine neurons and their alterations in a LRRK2G2019S model of Parkinson's disease

Several studies have revealed that midbrain dopamine (DA) neurons, even within a single neuroanatomical area, display heterogeneous properties. In parallel, studies using single cell profiling techniques have begun to cluster DA neurons into subtypes based on their molecular signatures. Recent work has shown that molecularly defined DA subtypes within the substantia nigra (SNc) display distinctive anatomic and functional properties, and differential vulnerability in Parkinsons disease (PD). Based on these provocative results, a granular understanding of these putative subtypes and their alterations in PD models, is imperative. We developed an optimized pipeline for single-nuclear RNA sequencing (snRNA-seq) and generated a high-resolution hierarchically organized map revealing 20 molecularly distinct DA neuron subtypes belonging to three main families. We integrated this data with spatial MERFISH technology to map, with high definition, the location of these subtypes in the mouse midbrain, revealing heterogeneity even within neuroanatomical sub-structures. Finally, we demonstrate that in the preclinical LRRK2G2019S knock-in mouse model of PD, subtype organization and proportions are preserved. Transcriptional alterations occur in many subtypes including those localized to the ventral tier SNc, where differential expression is observed in synaptic pathways, which might account for previously described DA release deficits in this model. Our work provides an advancement of current taxonomic schemes of the mouse midbrain DA neuron subtypes, a high-resolution view of their spatial locations, and their alterations in a prodromal mouse model of PD. Teaser: Using snRNASeq and MERFISH we identified midbrain DA subtypes, mapped their spatial location, and identified alterations in a LRRK2 model

neuroscience↗

bioRxiv2023

Lateral entorhinal cortex subpopulations represent experiential epochs surrounding reward

During goal-directed navigation, "what" information, which describes the experiences occurring in periods surrounding a reward, can be combined with spatial "where" information to guide behavior and form episodic memories1,2. This integrative process is thought to occur in the hippocampus3, which receives spatial information from the medial entorhinal cortex (MEC)4; however, the source of the "what" information and how it is represented is largely unknown. Here, by establishing a novel imaging method, we show that the lateral entorhinal cortex (LEC) of mice represents key experiential epochs during a reward-based navigation task. We discover a population of neurons that signals goal approach and a separate population of neurons that signals goal departure. A third population of neurons signals reward consumption. When reward location is moved, these populations immediately shift their respective representations of each experiential epoch relative to reward, while optogenetic inhibition of LEC disrupts learning of the new reward location. Together, these results indicate the LEC provides a stable code of experiential epochs surrounding and including reward consumption, providing reward-centric information to contextualize the spatial information carried by the MEC. Such parallel representations are well-suited for generating episodic memories of rewarding experiences and guiding flexible and efficient goal-directed navigation5-7.

neuroscience↗

bioRxiv2022

Unique functional responses differentially map onto genetic subtypes of dopamine neurons

Dopamine neurons are characterized by their response to unexpected rewards, but they also fire during movement and aversive stimuli. Dopamine neuron diversity has been observed based on molecular expression profiles; however, whether different functions map onto such genetic subtypes remains unclear. Here, we establish that three genetic dopamine subtypes within the substantia nigra pars compacta each have a unique set of responses to rewards, aversive stimuli, accelerations and decelerations, and these signaling patterns are highly-correlated between somas and axons within subtypes. Remarkably, reward responses were not detected in one subtype, which instead displayed acceleration-correlated signaling. Our findings establish a connection between functional and genetic dopamine subtypes and demonstrate that molecular expression patterns can serve as a common framework to dissect dopaminergic functions.

neuroscience↗

bioRxiv2022

Dopaminergic axons track somatic signaling in behaving mice

Striatal dopamine released from the axons of midbrain dopamine neurons has been linked to a wide range of functions, including movement control and reward-based learning. Recent studies have reported functional signaling differences between axons and somas of dopamine neurons, suggesting that local modulation controls dopamine release and calling into question the classical view of somatic control. However, these experiments are technically challenging, making it difficult to ensure that axonal and somatic recordings come from the same neurons, particularly given the heterogeneity of dopaminergic cell types. Here we used genetic strategies to isolate key dopaminergic neuron subtypes and monitor their axonal and somatic signaling patterns in behaving mice. Contrary to the inferences drawn from previous studies, these experiments revealed a robust correlation between somatic and axonal signaling. Thus, by exploiting a previously unknown connection between genetic and functional diversity in dopamine neurons, we establish that subtypes must be considered to understand the mechanisms of dopamine release in striatum during behavior.

neuroscience↗

bioRxiv2020

Information theoretic approaches to deciphering the neural code with functional fluorescence imaging

Information theoretic metrics have proven useful in quantifying the relationship between behaviorally relevant parameters and neuronal activity with relatively few assumptions. However, these metrics are typically applied to action potential recordings and were not designed for the slow timescales and variable amplitudes typical of functional fluorescence recordings (e.g. calcium imaging). The lack of research guidelines on how to apply and interpret these metrics with fluorescence traces means the neuroscience community has yet to realize the power of information theoretic metrics. Here, we used computational methods to create mock action potential traces with known amounts of information. From these, we generated fluorescence traces and examined the ability of different information metrics to recover the known information values. We provide guidelines for how to use information metrics when applying them to functional fluorescence and demonstrate their appropriate application to GCaMP6f population recordings from mouse hippocampal neurons imaged during virtual navigation.

neuroscience↗