Local accumbens in vivo imaging during deep brain stimulation reveals a strategy-dependent amelioration of hedonic feeding

Wu, Hemmings; Kakusa, Bina; Neuner, Sophie; Christoffel, Daniel J.; Heifets, Boris D.; Malenka, Robert C.; Halpern, Casey H.

doi:10.1073/pnas.2109269118

Cited by 15 publications

(9 citation statements)

References 48 publications

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“…Perhaps, the neuropeptides released by PSTN Tac1 neurons cause a sustained change in neural activity in downstream neural populations. Indeed, many other neural populations that affect food intake behavior also show a transient increase in neural activity on the timescale of seconds ( Berrios et al, 2021 ; Luskin et al, 2021 ; Mohammad et al, 2021 ; Wu et al, 2022 ). Alternatively, perhaps PSTN Tac1 neurons exhibit a transient increase in activity but do not completely return to baseline levels over a sustained period in a way that is not detectable by fiber photometry.…”

Section: Discussionmentioning

confidence: 99%

A discrete parasubthalamic nucleus subpopulation plays a critical role in appetite suppression

Kim

Kromm

Barnhill

et al. 2022

eLife

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Food intake behavior is regulated by a network of appetite-inducing and appetite-suppressing neuronal populations throughout the brain. The parasubthalamic nucleus (PSTN), a relatively unexplored population of neurons in the posterior hypothalamus, has been hypothesized to regulate appetite due to its connectivity with other anorexigenic neuronal populations and because these neurons express Fos, a marker of neuronal activation, following a meal. However, the individual cell types that make up the PSTN are not well characterized, nor are their functional roles in food intake behavior. Here we identify and distinguish between two discrete PSTN subpopulations, those that express tachykinin-1 (PSTNTac1 neurons) and those that express corticotropin-releasing hormone (PSTNCRH neurons), and use a panel of genetically encoded tools in mice to show that PSTNTac1 neurons play an important role in appetite suppression. Both subpopulations increase activity following a meal and in response to administration of the anorexigenic hormones amylin, cholecystokinin (CCK), and peptide YY (PYY). Interestingly, chemogenetic inhibition of PSTNTac1, but not PSTNCRH neurons, reduces the appetite-suppressing effects of these hormones. Consistently, optogenetic and chemogenetic stimulation of PSTNTac1 neurons, but not PSTNCRH neurons, reduces food intake in hungry mice. PSTNTac1 and PSTNCRH neurons project to distinct downstream brain regions, and stimulation of PSTNTac1 projections to individual anorexigenic populations reduces food consumption. Taken together, these results reveal the functional properties and projection patterns of distinct PSTN cell types and demonstrate an anorexigenic role for PSTNTac1 neurons in the hormonal and central regulation of appetite.

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Section: Discussionmentioning

confidence: 99%

A discrete parasubthalamic nucleus subpopulation plays a critical role in appetite suppression

Kim

Kromm

Barnhill

et al. 2022

eLife

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“…To characterize the network effect of DBS, Paulk et al mapped the cortical responses evoked by single-pulse electrical stimulation delivered via intracranial electrodes in epilepsy patients and confirmed that DBS evoked broad network responses that were stimulation location and pulse parameter dependent 26 . Finally, using cellular fluorescent calcium imaging techniques, a couple of recent studies in animal models demonstrated that DBS altered the relationship of intracellular calcium dynamics and behavior, supporting a network effect of DBS [27][28][29] .…”

mentioning

confidence: 90%

Deep brain stimulation creates informational lesion through membrane depolarization in mouse hippocampus

et al. 2022

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Deep brain stimulation (DBS) is a promising neuromodulation therapy, but the neurophysiological mechanisms of DBS remain unclear. In awake mice, we performed high-speed membrane voltage fluorescence imaging of individual hippocampal CA1 neurons during DBS delivered at 40 Hz or 140 Hz, free of electrical interference. DBS powerfully depolarized somatic membrane potentials without suppressing spike rate, especially at 140 Hz. Further, DBS paced membrane voltage and spike timing at the stimulation frequency and reduced timed spiking output in response to hippocampal network theta-rhythmic (3–12 Hz) activity patterns. To determine whether DBS directly impacts cellular processing of inputs, we optogenetically evoked theta-rhythmic membrane depolarization at the soma. We found that DBS-evoked membrane depolarization was correlated with DBS-mediated suppression of neuronal responses to optogenetic inputs. These results demonstrate that DBS produces powerful membrane depolarization that interferes with the ability of individual neurons to respond to inputs, creating an informational lesion.

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“…In both of these methods, there are issues concerning detection sensitivity and selectivity of neurotransmitters, molecular inaccuracy or, for instance, the impossibility to target electrochemically inert s ubstances, such as glutamate, or to conduct chronic (e.g., 2–6 weeks) studies. So far, a single fiber photometric study has explored the mediated DBS effects integrating photometric readouts, although stimulating and recording directly in the NAc in the context of a model of eating disorders [ 42 ], hence also showing the novelty of this technique to elucidate DBS mechanisms in an electrical artifact free recording platform.…”

Section: Discussionmentioning

confidence: 99%

New Insights into In Vivo Dopamine Physiology and Neurostimulation: A Fiber Photometry Study Highlighting the Impact of Medial Forebrain Bundle Deep Brain Stimulation on the Nucleus Accumbens

et al. 2022

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New technologies, such as fiber photometry, can overcome long-standing methodological limitations and promote a better understanding of neuronal mechanisms. This study, for the first time, aimed at employing the newly available dopamine indicator (GRABDA2m) in combination with this novel imaging technique. Here, we present a detailed methodological roadmap leading to longitudinal repetitive transmitter release monitoring in in vivo freely moving animals and provide proof-of-concept data. This novel approach enables a fresh look at dopamine release patterns in the nucleus accumbens, following the medial forebrain bundle (mfb) DBS in a rodent model. Our results suggest reliable readouts of dopamine levels over at least 14 days of DBS-induced photometric measurements. We show that mfb-DBS can elicit an increased dopamine response during stimulation (5 s and 20 s DBS) compared to its baseline dopamine activity state, reaching its maximum peak amplitude in about 1 s and then recovering back after stimulation. The effect of different DBS pulse widths (PWs) also suggests a potential differential effect on this neurotransmitter response, but future studies would need to verify this. Using the described approach, we aim to gain insights into the differences between pathological and healthy models and to elucidate more exhaustively the mechanisms under which DBS exerts its therapeutic action.

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Local accumbens in vivo imaging during deep brain stimulation reveals a strategy-dependent amelioration of hedonic feeding

Cited by 15 publications

References 48 publications

A discrete parasubthalamic nucleus subpopulation plays a critical role in appetite suppression

A discrete parasubthalamic nucleus subpopulation plays a critical role in appetite suppression

Deep brain stimulation creates informational lesion through membrane depolarization in mouse hippocampus

New Insights into In Vivo Dopamine Physiology and Neurostimulation: A Fiber Photometry Study Highlighting the Impact of Medial Forebrain Bundle Deep Brain Stimulation on the Nucleus Accumbens

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