Biology subjects

Miranda-Barrientos, J.

Publications and source records attributed to Miranda-Barrientos, J..

4 recordsLinked to original sources

bioRxiv2025

Top-down control of sustained attention by the medial prefrontal cortex (mPFC)- locus coeruleus (LC) circuit during the rodent continuous performance task (rCPT)

The medial prefrontal cortex (mPFC) plays a pivotal role in attention by exerting top-down control to allocate cognitive resources toward behaviorally relevant stimuli based on learned context and expectations. mPFC neurons project to multiple cortical and subcortical regions, including the locus coeruleus (LC)--the brains primary source of norepinephrine (NE). The mPFC also receives inputs from the LC, which release NE to modulate mPFC neuronal activity and downstream cellular signaling. While enhanced functional connectivity between the mPFC and LC in mice during sustained attention tasks suggest an important role for the mPFC-LC circuit, functional evidence directly implicating this circuit in attention is lacking. Here, we investigated the role of the mPFC-LC circuit in attention by comparing selective chemogenetic manipulation of mPFC neurons that project to the LC (mPFC-LC projectors) to non-specific chemogenetic manipulation of mPFC neurons. Selective activation of mPFC-LC projectors in mice performing the rodent continuous performance test (rCPT), a translational sustained attention task, robustly improves attentional performance by enhancing discrimination while non-selective activation of mPFC neurons increases attentional performance by increasing responsiveness. Behavioral effects of mPFC-LC projector activation were mediated by recruitment of a microcircuit involving LC-NE neurons and glutamate and GABA peri-LC neurons while effects of non-selective activation of mPFC neurons were mediated by engaging downstream targets such as the nucleus accumbens (NAc) as well as the LC/peri-LC region.

neuroscience↗

bioRxiv2024

Time-on-task-related decrements in performance in the rodent continuous performance test are not caused by physical disengagement from the task

Attention deficits, a hallmark of many neuropsychiatric disorders, significantly impair quality of life and functional outcome for patients. Continuous Performance Tests (CPTs) are widely used to assess attentional function in clinical settings and have been adapted for mice as the rodent Continuous Performance Test (rCPT). In this study, we combined traditional analyses of rCPT performance with markerless pose estimation using DeepLabCut and visual field analysis (VFA) to objectively measure the orientation of mice toward stimuli during rCPT sessions. Additionally, we extended session lengths to assess performance decrements over time. Our findings show that extending rCPT sessions from 45 to 90 minutes results in a significant decline in performance in male mice, which aligns with performance decrements observed in clinical research. Importantly, physical engagement with the task remained relatively stable throughout the session, even as performance deteriorated. This suggests that the performance decline specifically reflects a time-on-task (TOT)-dependent vigilance decrement rather than physical disengagement. We also investigated the effects of amphetamine, an FDA-approved treatment for attention-deficit/hyperactivity disorder (ADHD), on rCPT performance. Amphetamine significantly improved rCPT performance in male mice by reducing false alarms without modulating orientation or physical engagement with the task stimuli. Collectively, these findings validate a behavioral tracking platform for objectively measuring physical engagement in the rCPT and a task modification that accentuates TOT-dependent performance decrements, enhancing the translational value of the rCPT for studies related to human neuropsychiatric disorders.

neuroscience↗

bioRxiv2023

Electrophysiological correlates of attention in the locus coeruleus - anterior cingulate cortex circuit during the rodent continuous performance test

Sustained attention, the ability to focus on an activity or stimulus over time, is significantly impaired in many psychiatric disorders, and there remains a major unmet need in treating impaired attention. Continuous performance tests (CPTs) were developed to measure sustained attention in humans, non-human primates, rats, and mice, and similar neural circuits are engaged across species during CPT performance, supporting their use in translational studies to identify novel therapeutics. Here, we identified electrophysiological correlates of attentional performance in a touchscreen-based rodent CPT (rCPT) in the locus coeruleus (LC) and anterior cingulate cortex (ACC), two inter-connected regions that are implicated in attentional processes. We used viral labeling and molecular techniques to demonstrate that neural activity is recruited in LC-ACC projections during the rCPT, and that this recruitment increases with cognitive demand. We implanted male mice with depth electrodes within the LC and ACC for local field potential (LFP) recordings during rCPT training, and identified an increase in ACC delta and theta power, and an increase in LC delta power during correct responses in the rCPT. We also found that the LC leads the ACC in theta frequencies during correct responses while the ACC leads the LC in gamma frequencies during incorrect responses. These findings may represent translational biomarkers that can be used to screen novel therapeutics for drug discovery in attention.

neuroscience↗

bioRxiv2021

ACUTE FOOD DEPRIVATION DECREASES THE EXPRESSION OF METHAMPHETAMINE-INDUCED LOCOMOTOR SENSITIZATION IN RATS

INTRODUCTIONAMPH and METH are known to increase DAergic signaling in the brain reward system by stimulating the release of DA through the reversal of DAT function. However, there is evidence that insulin signaling pathways have the ability to modulate DAT functions. Some studies have reported that hypoinsulinemia attenuates DAT functions, and as a consequence, psychostimulant-induced behaviors are reduced. In the present study, we examined the effects of acute food deprivation, which also reduces insulin levels, on METH-induced locomotor sensitization. METHODSSeparate groups of rats were treated with METH (1 mg/kg i.p.) or saline for 5 days (development phase). On the test day (expression phase), the groups were treated with METH or saline after food deprivation for 24 h. Furthermore, in separate groups of rats, levels of glucose, insulin, and phosphorylation of Akt at Ser473 were also examined after food deprivation for 24 h. RESULTSThe results showed that repeated administration of METH induced a progressive increase in locomotor activity in rats during the development phase. However, METH administration in the expression phase produced a decrease in locomotor activity after 24 h of food deprivation. In addition, the results showed that a reduction in glucose, insulin, and Akt levels occurred as a result of food deprivation. CONCLUSIONThese results are in line with previous studies and suggest that food deprivation reduces some behavioral effects of psychostimulants such as AMPH and METH. HighlightsAdministration of METH increases DAergic neurotransmission by interfering with proper DA transporter (DAT) function Some evidence suggests that insulin signaling pathways modulate the DAT in the brain reward system Acute food deprivation reduces glucose and insulin levels This study examined the effects of acute food deprivation on METH-induced locomotor sensitization Present study showed that food deprivation for 24 h reduced METH-induced locomotor sensitization Plain Language SummaryThe dopamine transporter (DAT) is responsible for the reuptake of dopamine (DA) and the termination of DA neurotransmission. DAT is also the target for psychostimulant drugs such as cocaine, amphetamine, and methamphetamine. These drugs produce an increase of DA neurotransmission in the reward system. It is now well established that insulin levels modulate DAT function. Several studies have reported that hypoinsulinemia attenuates DAT function, and as a consequence, psychostimulant-induced behaviors are reduced. Food deprivation reduces glucose and insulin levels. In the present study we evaluated the effects of food deprivation on methamphetamine-induced locomotor sensitization. This behavior reflects brain neuroadaptations that contribute to drug addiction. Rats of the main experimental group were treated with methamphetamine for 5 days (development phase). On the test day (expression phase) the rats were treated with methamphetamine after food deprivation for 24 h. In separated groups of rats levels of glucose and insulin were evaluated after food deprivation for 24 h. The results showed that acute food deprivation reduced methamphetamine-induced locomotor sensitization. It was also observed that insulin and glucose levels were reduced after food deprivation. The results of the present study suggest that food deprivation can modulate some behavioral effects of methamphetamine.

neuroscience↗