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Pinto, L.

Publications and source records attributed to Pinto, L..

27 records · Page 2Linked to original sources

Change point estimation by the mouse medial frontal cortex during probabilistic reward learning

There are often sudden changes in the state of environment. For a decision maker, accurate prediction and detection of change points are crucial for optimizing performance. Still unclear, however, is whether rodents are simply reactive to reinforcements, or if they can be proactive to estimate future change points during value-based decision making. In this study, we characterize head-fixed mice performing a two-armed bandit task with probabilistic reward reversals. Choice behavior deviates from classic reinforcement learning, but instead suggests a strategy involving belief updating, consistent with the anticipation of change points to exploit the task structure. Excitotoxic lesion and optogenetic inactivation implicate the anterior cingulate and premotor regions of medial frontal cortex. Specifically, over-estimation of hazard rate arises from imbalance across frontal hemispheres during the time window before the choice is made. Collectively, the results demonstrate that mice can capitalize on their knowledge of task regularities, and this estimation of future changes in the environment may be a main computational function of the rodent dorsal medial frontal cortex.

neuroscience↗

Involvement of nucleus accumbens D2-MSN projections to the ventral pallidum in anxious-like behavior

The nucleus accumbens (NAc) is a crucial brain region for emotionally-relevant behaviors. The NAc is mainly composed of medium spiny neurons (MSN) expressing either dopamine receptor D1 (D1-MSNs) or D2 (D2-MSNs). D1-MSNs project to the ventral tegmental area (VTA) and ventral pallidum (VP), while D2-MSNs project only to the VP. In this work, we selectively manipulated D1-MSN projections to the VP and VTA, and D2-MSN projections to the VP during classical anxiety behavioral paradigms in naive mice. We found that optogenetic activation of D1-MSN to VP or VTA did not trigger significant anxious-like behaviors. Interestingly, optical activation of D2-MSN-VP projections significantly increased anxious-like behavior in all of the tests performed. This phenotype was associated with a decrease in the activity of VP putative GABAergic neurons. Importantly, pre-treating D2-MSN-VP animals with the GABA modulator diazepam prevented the optically-triggered anxious-like behavior. Overall, our results suggest that D2-MSN-VP projections contribute for the development of anxious-like behavior, through modulation of GABAergic activity in the VP.

neuroscience↗

Strong and opponent contributions of dorsomedial striatal pathways to behavior depends on cognitive demands and task strategy

A classic view of the striatum holds that activity in direct and indirect pathways oppositely modulates motor output. Whether this involves direct control of movement, or reflects a cognitive process underlying movement, remains unresolved. Here we find that strong, opponent control of behavior by the two pathways of the dorsomedial striatum (DMS) depends on the cognitive requirements of a task. Furthermore, a latent state model (a hidden markov model with generalized linear model observations) reveals that--even within a single task--the contribution of the two pathways to behavior is state-dependent. Specifically, the two pathways have large contributions in one of two states associated with a strategy of evidence accumulation, compared to a state associated with a strategy of repeating previous choices. Thus, both the demands imposed by a task, as well as the internal state of mice when performing a task, determine whether DMS pathways provide strong and opponent control of behavior.

neuroscience↗

Constitutive AP2gamma deficiency reduces postnatal hippocampal neurogenesis and induces behavioral deficits in juvenile mice that persist during adulthood

The transcription factor activating protein two gamma (AP2{gamma}) is an important regulator of neurogenesis both during embryonic development as well as in the postnatal brain, but its role for neurophysiology and behavior at distinct postnatal periods is still unclear. In this work, we explored the neurogenic, behavioral, and functional impact of a constitutive AP2{gamma} heterozygous deletion in mice from early postnatal development until adulthood. Constitutive AP2{gamma} heterozygous deletion in mice caused a reduction of hippocampal transient amplifying progenitors (TAPs) in the postnatal brain, inducing significant impairments on hippocampal-dependent emotional- and cognitive-behavioral tasks including anxiety-like behavior and cognitive deficits, typically associated with an intact neurogenic activity. Moreover, AP2{gamma} deficiency impairs dorsal hippocampus-to-prefrontal cortex functional connectivity. We observed a progressive and cumulative impact of constitutive AP2{gamma} deficiency on the hippocampal glutamatergic neurogenic process, as well as alterations on limbic-cortical connectivity, together with impairments on emotional and cognitive behaviors from juvenile to adult periods. Collectively, the results herein presented demonstrate the importance of AP2{gamma} in the generation of glutamatergic neurons in the postnatal brain and its impact on behavioral performance.

neuroscience↗

Multiple timescales of sensory-evidence accumulation across the dorsal cortex

Cortical areas seem to form a hierarchy of intrinsic timescales, but whether this is causal to cognitive behavior remains unknown. In particular, decisions requiring the gradual accrual of sensory evidence over time recruit widespread areas across this hierarchy. Here, we causally tested the hypothesis that this recruitment is related to the intrinsic integration timescales of these widespread areas. We trained mice to accumulate evidence over seconds while navigating in virtual reality, and optogenetically silenced the activity of many cortical areas during different brief trial epochs. We found that the inactivation of different areas primarily affected the evidence-accumulation computation per se, rather than other decision-related processes. Specifically, we observed selective changes in the weighting of evidence over time, such that frontal inactivations led to deficits on longer timescales than posterior cortical ones. Likewise, large-scale cortical Ca2+ activity during task performance displayed different temporal integration windows matching the effects of inactivation. Our findings suggest that distributed cortical areas accumulate evidence by leveraging their hierarchy of intrinsic timescales.

neuroscience↗

Distinct role of nucleus accumbens D2-MSN projections to ventral pallidum in different phases of motivated behavior

The nucleus accumbens (NAc) is a key region in motivated behaviors. NAc medium spiny neurons (MSNs) are divided into those expressing dopamine receptor D1 or D2. Classically, D1- and D2-MSNs have been described as having opposing roles in reinforcement but recent evidence suggests a more complex role for D2-MSNs. Here we show that optogenetic modulation of D2-MSN to ventral pallidum (VP) projections during different stages of motivated behavior has contrasting effects in motivation. Activation of D2-MSN-VP projections during a reward-predicting cue results in increased motivational drive, whereas activation at reward delivery results in decreased motivation; optical inhibition has the opposite behavioral effect. In addition, in a free choice instrumental task, animals prefer the lever that originates one pellet in opposition to pellet plus D2-MSN-VP optogenetic activation, and vice versa for optogenetic inhibition. In summary, D2-MSN-VP projections play different (and even opposing) roles in distinct phases of motivated behavior.

neuroscience↗

XAB2 prevents abortive recombinational repair of replication-associated DNA double-strand breaks and its loss is synthetic lethal with RAD52 inhibition

Unrepaired O6-methylguanine lesions induced by the alkylating chemotherapy agent temozolomide lead to replication-associated single-ended DNA double-strand breaks (seDSBs) that are repaired predominantly through RAD51-mediated homologous recombination (HR). Here, we show that loss of the pre-mRNA splicing and DNA repair protein XAB2 leads to increased temozolomide sensitivity in glioblastoma cells, which reflects abortive HR due to Ku retention on resected seDSBs. XAB2-dependent Ku eviction also occurred at seDSBs generated by the topoisomerase I poison campthotecin and operated in parallel to an ATM-dependent pathway previously described. Although Ku retention elicited by loss of XAB2 did not prevent RAD51 focus formation, the resulting RAD51-ssDNA associations were unproductive, leading to increased engagement of non-homologous-end-joining in S/G2 and genetic instability. Overexpression of RAD51 or the single-stranded DNA annealing factor RAD52 rescued the XAB2 defects. RAD52 depletion led to severe temozolomide sensitivity, whereas a synthetic lethality interaction was observed between RAD52 and XAB2.

molecular biology↗

Clues on an intraspecific communication system in early plant establishment: The seed-seedling transition from the point of view of a crosstalk between information theory and gene expression

How much interactivity is there in a seed-seedling transition system? The answer for this question can reveal a key aspect for early plant establishment. Thus, we hypothesize that information entropy is correlated with early plant development because it is directly related to interactions between seed-seed, seed-seedling, and seedling-seedling. To test this hypothesis, we perform an overlapping of classical physiological measurements (embryo protrusion), gene expression in germination sensu stricto, water dynamics in germinating seeds and information theory. For a biological model, we used Solanum lycocarpum A. St.{square}Hil. seeds. This is a Neotropical species with high intra-specific variability in the seed sample. Our finds demonstrate that the dynamic and transient seed-seedling transition system is influenced by the number of individuals (seed or seedling) in the sample, especially at a same physiological stage. In addition, we also discuss that: (i) information entropy enables the quantification of system disturbance relative to individuals in the same physiological stage (seed-seed or seedling-seedling), which may be determinant for embryo growth during germination. (ii) there is possible intraspecific communication in seed-seedling transition systems formed by germinating seeds with the potential to alter the pattern of embryonic development of the sample. In view of this, we suggest the use of information entropy as a tool for studies of biological systems to clarify the phenomenon of mutual stimulation in the germination process.

plant biology↗

An accumulation-of-evidence task using visual pulses for mice navigating in virtual reality

The gradual accumulation of sensory evidence is a crucial component of perceptual decision making, but its neural mechanisms are still poorly understood. Given the wide availability of genetic and optical tools for mice, they can be useful model organisms for the study of these phenomena; however, behavioral tools are largely lacking. Here, we describe a new evidence-accumulation task for head-fixed mice navigating in a virtual reality environment. As they navigate down the stem of a virtual T-maze, they see brief pulses of visual evidence on either side, and retrieve a reward on the arm with the highest number of pulses. The pulses occur randomly with Poisson statistics, yielding a diverse yet well-controlled stimulus set, making the data conducive to a variety of computational approaches. A large number of mice of different genotypes were able to learn and consistently perform the task, at levels similar to rats in analogous tasks. They are sensitive to side differences of a single pulse, and their memory of the cues is stable over time. Moreover, using non-parametric as well as modeling approaches, we show that the mice indeed accumulate evidence: they use multiple pulses of evidence from throughout the cue region of the maze to make their decision, albeit with a small overweighting of earlier cues, and their performance is affected by the magnitude but not the duration of evidence. Additionally, analysis of the mice's running patterns revealed that trajectories are fairly stereotyped yet modulated by the amount of sensory evidence, suggesting that the navigational component of this task may provide a continuous readout correlated to the underlying cognitive variables. Our task, which can be readily integrated with state-of-the-art techniques, is thus a valuable tool to study the circuit mechanisms and dynamics underlying perceptual decision making, particularly under more complex behavioral contexts.

neuroscience↗