Biology subjects

Trujillo-Pisanty, I.

Publications and source records attributed to Trujillo-Pisanty, I..

6 recordsLinked to original sources

bioRxiv2025

Optogenetic stimulation of nigral astrocytes is neuroprotective in a 6-OHDA model of neurodegeneration.

HighlightsO_LIOptogenetic stimulation of nigral astrocytes attenuates motor deficits & Th+ cell loss in a 6-OHDA model of neurodegeneration C_LIO_LIBulk RNA-seq analysis reveals optogenetic stimulation of nigral astrocytes induces early changes in microglia C_LIO_LIsnRNA-seq shows 6-OHDA alone induces extensive gene expression changes across all cell populations within the SN C_LIO_LIOligodendrocytes within the SNc express Th, which is upregulated with DA neuron loss C_LI Parkinsons disease is characterized by the loss of dopaminergic neurons in the substantia nigra. Glial-glial crosstalk is essential for maintaining the regional milieu, and appears to be particularly important in modulating neuroinflammation and many aspects of neurodegeneration. In particular, astrocytes are critical for maintaining dopamine neuronal integrity and survival, and astroglial dysfunction is prominent in Parkinsons disease. As such, astrocytes represent a potentially critical therapeutic target in neurodegeneration. In this study, in vivo optogenetics were used to selectively stimulate astrocytes in the substantia nigra following a striatal 6-OHDA lesion. Remarkably, a single bout of optogenetic stimulation was sufficient to attenuate motor deficits and dopamine neuron loss induced by the neurotoxin. Furthermore, bulk RNA-seq and snRNA-seq analysis of the substantia nigra revealed extensive changes in both microglia and oligodendrocytes, suggesting that the neuroprotective effects of stimulating astrocytes may be mediated through alterations in glia-glia crosstalk. Altogether, this work demonstrates the importance of understanding glia-glia interactions in neurodegeneration.

neuroscience↗

bioRxiv2022

Does phasic dopamine release cause policy updates?

Phasic dopamine activity is believed to both encode reward-prediction errors (RPEs) and to cause the adaptations that these errors engender. If so, a rat working for optogenetic stimulation of dopamine neurons will repeatedly update its policy and/or action values, thus iteratively increasing its work rate. Here, we challenge this view by demonstrating stable, non-maximal work rates in the face of repeated optogenetic stimulation of midbrain dopamine neurons. Furthermore, we show that rats learn to discriminate between world states distinguished only by their history of dopamine activation. Comparison of these results to reinforcement learning simulations suggests that the induced dopamine transients acted more as rewards than RPEs. However, pursuit of dopaminergic stimulation drifted upwards over a time scale of days and weeks, despite its stability within trials. To reconcile the results with prior findings, we consider multiple roles for dopamine signaling.

neuroscience↗

bioRxiv2020

Drug self-administration in head-restrained mice for simultaneous multiphoton imaging

Multiphoton microscopy is one of several new technologies providing unprecedented insight into the activity dynamics and function of neural circuits. Unfortunately, many of these technologies require experimentation in head-restrained animals, greatly limiting the behavioral repertoire that can be studied with each approach. This issue is especially evident in drug addiction research, as no laboratories have coupled multiphoton microscopy with simultaneous intravenous drug self-administration, the gold standard of behavioral paradigms for investigating the neural mechanisms of drug addiction. Such experiments would be transformative for addiction research as one could measure or perturb an array of behavior and drug-related adaptations in precisely defined neural circuit elements over time, including but not limited to dendritic spine plasticity, neurotransmitter release, and neuronal activity. Here, we describe a new experimental assay wherein mice self-administer drugs of abuse while head-restrained, allowing for simultaneous multiphoton imaging. We demonstrate that this approach enables longitudinal tracking of activity in single neurons from the onset of drug use to relapse. The assay can be easily replicated by interested labs for relatively little cost with readily available materials and can provide unprecedented insight into the neural underpinnings of substance use disorder.

neuroscience↗

bioRxiv2020

Meta-reinforcement learning in a thalamo-orbitofrontal circuit

Learning to predict rewards is essential for the sustained fitness of animals. Contemporary views suggest that such learning is driven by a reward prediction error (RPE) -- the difference between received and predicted rewards. The magnitude of learning induced by an RPE is proportional to the product of the RPE and a learning rate. Here we demonstrate using two- photon calcium imaging and optogenetics in mice that certain functionally distinct subpopulations of ventral/medial orbitofrontal cortex (vmOFC) neurons signal learning rate control. Consistent with learning rate control, trial-by-trial fluctuations in vmOFC activity positively correlates with behavioral updating when RPE is positive, and negatively correlates with behavioral updating when RPE is negative. Learning rate is affected by many variables including the salience of a reward. We found that the average reward response of these neurons signals the relative salience of a reward, as it decreases after reward prediction learning or the introduction of another highly salient aversive stimulus. The relative salience signaling in vmOFC is sculpted by medial thalamic inputs. These results support emerging theoretical views that the prefrontal cortex encodes and controls learning parameters.

neuroscience↗

bioRxiv2019

The effect of dopamine transporter blockade on optical self-stimulation: behavioral and computational evidence for parallel processing in brain reward circuitry

The neurobiological study of reward was launched by the discovery of intracranial self-stimulation (ICSS). Subsequent investigation of this phenomenon provided the initial link between reward-seeking behavior and dopaminergic neurotransmission. We re-evaluated this relationship by psychophysical, pharmacological, optogenetic, and computational means. In rats working for direct, optical activation of midbrain dopamine neurons, we varied the strength and opportunity cost of the stimulation and measured time allocation, the proportion of trial time devoted to reward pursuit. We found that the dependence of time allocation on the strength and cost of stimulation was similar formally to that observed when electrical stimulation of the medial forebrain bundle served as the reward. When the stimulation is strong and cheap, the rats devote almost all their time to reward pursuit; time allocation falls off as stimulation strength is decreased and/or its opportunity cost is increased. A 3D plot of time allocation versus stimulation strength and cost produces a surface resembling the corner of a plateau (the "reward mountain"). We show that dopamine-transporter blockade shifts the mountain along both the strength and cost axes in rats working for optical activation of midbrain dopamine neurons. In contrast, the same drug shifted the mountain uniquely along the opportunity-cost axis when rats worked for electrical MFB stimulation in a prior study. Dopamine neurons are an obligatory stage in the dominant model of ICSS, which positions them at a key nexus in the final common path for reward seeking. This model fails to provide a cogent account for the differential effect of dopamine transporter blockade on the reward mountain. Instead, we propose that midbrain dopamine neurons and neurons with non-dopaminergic, MFB axons constitute parallel limbs of brain-reward circuitry that ultimately converge on the final-common path for the evaluation and pursuit of rewards. Author summaryTo succeed in the struggle for survival and reproductive success, animals must make wise choices about which goals to pursue and how much to pay to attain them. How does the brain make such decisions and adjust behaviour accordingly? An animal model that has long served to address this question entails delivery of rewarding brain stimulation. When the probe is positioned appropriately in the brain, rats will work indefatigably to trigger such stimulation. Dopamine neurons play a crucial role in this phenomenon. The dominant model of the brain circuitry responsible for the reward-seeking behavior treats these cells as a gateway through which the reward-generating brain signals must pass. Here, we challenge this idea on the basis of an experiment in which the dopamine neurons were activated selectively and directly. Mathematical modeling of the results argues for a new view of the structure of brain reward circuitry. On this view, the pathway(s) in which the dopamine neurons are embedded is one of a set of parallel channels that process reward signals in the brain. To achieve a full understanding of how goals are evaluated, selected and pursued, the full set of channels must be identified and investigated.

neuroscience↗

bioRxiv2018

Divergent mesolimbic dopamine circuits support alcohol-seeking triggered by discrete cues and contexts

Discrete and contextual cues that predict alcohol trigger alcohol-seeking. However, the extent to which context influences alcohol-seeking triggered by discrete cues, and the neural mechanisms underlying these responses, are not well known. We show that, relative to a neutral context, a context associated with alcohol persistently elevated alcohol-seeking triggered by a discrete cue, and supported higher levels of priming-induced reinstatement. Alcohol-seeking triggered by a discrete cue in a neutral context was reduced by designer receptor-mediated inhibition of ventral tegmental area (VTA) dopamine neurons in TH::Cre rats. Inhibiting terminals of VTA dopamine neurons in the nucleus accumbens (NAc) core reduced alcohol-seeking triggered by a discrete cue, irrespective of context, whereas inhibiting VTA dopamine terminals in the NAc shell selectively reduced the elevation of alcohol-seeking triggered by a discrete cue in an alcohol context. This dissociation highlights unique roles for divergent mesolimbic dopamine circuits in alcohol-seeking driven by discrete and contextual environmental cues.

neuroscience↗