Biology subjects

Beier, K.

Publications and source records attributed to Beier, K..

3 recordsLinked to original sources

bioRxiv2022

Modified viral-genetic mapping reveals local and global connectivity relationships of ventral tegmental area dopamine cells

Dopamine cells in the ventral tegmental area (VTADA) are critical for a variety of motivated behaviors. These cells receive synaptic inputs from over 100 anatomically-defined brain regions, which enables control from a distributed set of inputs across the brain. Extensive efforts have been made to map inputs to VTA cells based on neurochemical phenotype and output site. However, all of these studies have the same fundamental limitation that inputs local to the VTA cannot be properly assessed due to non-Cre-dependent uptake of EnvA-pseudotyped virus. Therefore, the quantitative contribution of local inputs to the VTA, including GABAergic, DAergic, and serotonergic, is not known. Here, we used a modified viral-genetic strategy that enables examination of both local as well as long-range inputs to VTADA cells. We found that nearly half of the total inputs to VTADA cells are located locally, revealing a substantial portion of inputs that have been missed by previous analyses. The majority of inhibition to VTADA cells arises from the substantia nigra pars reticulata, with large contributions from the VTA and the substantia nigra pars compacta. In addition to receiving inputs from VTAGABA neurons, DA neurons are connected with other DA neurons within the VTA as well as the nearby retrorubal field. Lastly, we show that VTADA neurons receive inputs from distributed serotonergic neurons throughout the midbrain and hindbrain, with the majority arising from the dorsal raphe. Our study highlights the importance of using the appropriate combination of viral-genetic reagents to unmask the complexity of connectivity relationships to defined cells in the brain.

neuroscience↗

bioRxiv2021

An extended amygdala-midbrain circuit controlling cocaine withdrawal-induced anxiety and reinstatement

While midbrain dopamine (DA) neuronal circuits are central to motivated behaviors, much remains unknown about our knowledge of how these circuits are modified over time by experience to facilitate selective aspects of experience-dependent plasticity. Most studies of the DA system in drug addiction focus on the role of the mesolimbic DA pathway from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) in facilitating drug-associated reward. In contrast, less is known about how midbrain DA cells and associated circuits contribute to negative affective states including anxiety that emerge during protracted withdrawal from drug administration. Here, we demonstrate the selective role of a midbrain DA projection to the amygdala (VTADA[->]Amygdala) for anxiety that develops during protracted withdrawal from cocaine administration but does not participate in cocaine reward or sensitization. Our rabies virus-mediated circuit mapping approach revealed a persistent elevation in spontaneous and task-related activity of GABAergic cells from the bed nucleus of the stria terminals (BNST) and downstream VTADA[->]Amygdala cells that could be detected even after a single cocaine exposure. Activity in BNSTGABA cells was related to cocaine-induced anxiety but not reward or sensitization, and silencing the projection from these cells to the midbrain was sufficient to prevent the development of anxiety during protracted withdrawal following cocaine administration. We observed that VTADA[->]Amygdala cells, but not other midbrain DA cells, were strongly activated after a challenge exposure to cocaine, and found that activity in these cells was necessary for the expression of reinstatement of cocaine place preference. Lastly, the importance of activity in VTADA[->]Amygdala cells extends beyond cocaine, as these cells mediate the development of anxiety states triggered by morphine and a predator odor. Our results provide an exemplar for how to identify key circuit substrates that contribute to behavioral adaptations and reveal a critical role for BNSTGABA[->]VTADA[->]Amygdala pathway in anxiety states induced by drugs of abuse or natural experiences as well as cocaine-primed reinstatement of conditioned place preference.

neuroscience↗

bioRxiv2021

The Relationship between Birth Timing, Circuit Wiring, and Physiological ResponseProperties of Cerebellar Granule Cells

Cerebellar granule cells (GrCs) are usually regarded as a uniform cell type that collectively expands the coding space of the cerebellum by integrating diverse combinations of mossy fiber inputs. Accordingly, stable molecularly or physiologically defined GrC subtypes within a single cerebellar region have not been reported. The only known cellular properties that distinguishes otherwise homogeneous GrCs is the correspondence between GrC birthtime and the depth of the molecular layer to which their axons (parallel fibers) project. To determine the role birth timing plays in GrC wiring and function, we developed genetic strategies to access early- and late-born GrCs. We initiated retrograde monosynaptic rabies virus tracing from control, early-born, and late-born GrCs, revealing the different patterns of mossy fiber input to GrCs in vermis lobule 6 and simplex, as well as to early- and late-born GrCs of vermis lobule 6: sensory and motor nuclei provide more input to early-born GrCs, while basal pontine and cerebellar nuclei provide more input to late-born GrCs. In vivo multi-depth 2-photon Ca2+ imaging of parallel fibers of early- and late-born GrCs revealed representations of diverse task variables and stimuli by both populations, with differences in the proportions of parallel fibers encoding movement, reward anticipation, and reward consumption. Our results suggest neither organized parallel processing nor completely random organization of mossy fiber[->]GrC circuitry, but instead a moderate influence of birth timing on GrC wiring and encoding. Our imaging data also suggest that GrCs can represent general aversiveness, in addition to recently described reward representations. Significance StatementCerebellar granule cells (GrCs) comprise the majority of all neurons in the mammalian brain and are usually regarded as a uniform cell type. However, the birth timing of an individual GrC dictates where its axon projects. Using viral-genetic techniques, we find that early- and late-born GrCs receive different proportions of inputs from the same set of input regions. Using in vivo multi-depth 2-photon Ca2+ imaging of axons of early- and late-born GrCs, we found that both populations represent diverse task variables and stimuli, with differences in the proportions of axons in encoding of a subset of movement and reward parameters. These results indicate that birth timing contributes to the input selection and physiological response properties of GrCs.

neuroscience↗