Biology subjects

Ruiz, C. M.

Publications and source records attributed to Ruiz, C. M..

6 recordsLinked to original sources

bioRxiv2025

Ventral Pallidum GABA Neuron Inhibition Augments Context-Appropriate Defensive Responses to Learned Threat Cues

The ventral pallidum (VP) is embedded within the brain circuits controlling motivated behavior, which are heavily implicated in addiction and other psychiatric disorders. Prior work showed that VP GABAergic neurons (VPGABA) promote reward approach and seeking, while the intermixed population of VP glutamate neurons instead promote avoidance and aversion. Some have thus suggested a functional dichotomy between these VP subpopulations in reward versus threat. We test this hypothesis by asking how inhibiting VPGABA impacts active and passive defensive responses to learned threat cues in the absence of rewards. We taught GAD1:Cre rats with inhibitory VPGABA DREADDs (or control rats) that a metal probe delivers shock, or that a 20sec auditory cue precedes footshocks. These stimuli thereafter elicit active defensive burying, or passive freezing responses, respectively. We found that VPGABA inhibition with CNO markedly increased stimulus-appropriate defensive responses to both types of learned threats, but failed to consistently alter new learning about them--suggesting VPGABA mediates aversive motivation but not memory formation. VPGABA inhibition also altered threat-related c-Fos expression within VP cell populations, and in their efferent target lateral habenula, but not mediodorsal thalamus--pointing to potential underlying circuit mechanisms of defensive responses. Results indicate that VPGABA neurons not only promote reward seeking as previously reported, but that they may also actively inhibit defensive responses to threats that might otherwise compete with reward seeking. This refines our understanding of subcortical valanced motivation circuits, and may suggest new targets for intervening in disorders like addiction and depression. Highlights-Inhibiting VPGABA increases defenses against threatening stimuli -Both active (burying) and passive (freezing) responses were enhanced -Inhibiting VPGABA excites other VP cells, and neurons in downstream LHb -VP subpopulations may interact to bidirectionally modulate circuits and adaptive behaviors Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=114 SRC="FIGDIR/small/672918v2_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@1978f03org.highwire.dtl.DTLVardef@12e4d59org.highwire.dtl.DTLVardef@d81bfforg.highwire.dtl.DTLVardef@164261_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Adolescent THC impacts on mPFC dopamine-mediated cognitive processes in male and female rats

RationaleAdolescent cannabis use is linked to later-life changes in cognition, learning, and memory. Rodent experimental studies suggest {Delta}9-tetrahydrocannabinol (THC) influences development of circuits underlying these processes, especially in the prefrontal cortex, which matures during adolescence. ObjectiveWe determined how 14 daily THC injections (5mg/kg) during adolescence persistently impacts medial prefrontal cortex (mPFC) dopamine-dependent cognition. MethodsIn adult Long Evans rats treated as adolescents with THC (AdoTHC), we quantify performance on two mPFC dopamine-dependent reward-based tasks--strategy set shifting and probabilistic discounting. We also determined how acute dopamine augmentation with amphetamine (0, 0.25, 0.5 mg/kg), or specific chemogenetic stimulation of ventral tegmental area (VTA) dopamine neurons and their projections to mPFC impacts probabilistic discounting. ResultsAdoTHC sex-dependently impacts acquisition of cue-guided instrumental reward seeking, but has minimal effects on set-shifting or probabilistic discounting in either sex. When we challenged dopamine circuits acutely with amphetamine during probabilistic discounting, we found reduced discounting of improbable reward options, with AdoTHC rats being more sensitive to these effects than controls. In contrast, neither acute chemogenetic stimulation of VTA dopamine neurons nor pathway-specific chemogenetic stimulation of their projection to mPFC impacted probabilistic discounting in control rats, although stimulation of this cortical dopamine projection slightly disrupted choices in AdoTHC rats. ConclusionsThese studies confirm a marked specificity in the cognitive processes impacted by AdoTHC exposure. They also suggest that some persistent AdoTHC effects may alter amphetamine-induced cognitive changes in a manner independent of VTA dopamine neurons or their projections to mPFC.

animal behavior and cognition↗

bioRxiv2023

A head-to-head comparison of two DREADD agonists for suppressing operant behavior in rats via VTA dopamine neuron inhibition

RationaleDesigner receptors exclusively activated by designer drugs (DREADDs) are a tool for "remote control" of defined neuronal populations during behavior. These receptors are inert unless bound by an experimenter-administered designer drug, most commonly clozapine-n-oxide (CNO). However, questions have emerged about the suitability of CNO as a systemically administered DREADD agonist. ObjectivesSecond-generation agonists such as JHU37160 (J60) have been developed, which may have more favorable properties than CNO. Here we sought to directly compare effects of CNO (0, 1, 5, & 10 mg/kg, i.p.) and J60 (0, 0.03, 0.3, & 3 mg/kg, i.p.) on operant food pursuit. MethodsMale and female TH:Cre+ rats and their wildtype (WT) littermates received cre-dependent hM4Di-mCherry vector injections into ventral tegmental area (VTA), causing inhibitory DREADD expression in VTA dopamine neurons in TH:Cre+ rats. Rats were trained to stably lever press for palatable food on a fixed ratio 10 schedule, and doses of both agonists were tested on separate days in a counterbalanced order. ResultsAll three CNO doses reduced operant food seeking in rats with DREADDs, and no CNO dose had behavioral effects in WT controls. The highest tested J60 dose significantly reduced responding in DREADD rats, but this dose also increased responding in WTs, indicating non-specific effects. The magnitude of CNO and J60 effects in TH:Cre+ rats were correlated and were present in both sexes. ConclusionsFindings demonstrate the usefulness of directly comparing DREADD agonists when optimizing behavioral chemogenetics, and highlight the importance of proper controls, regardless of the DREADD agonist employed.

neuroscience↗

bioRxiv2020

Targeted cancer therapy induces APOBEC fuelling the evolution of drug resistance

Introductory paragraphThe clinical success of targeted cancer therapy is limited by drug resistance that renders cancers lethal in patients1-4. Human tumours can evolve therapy resistance by acquiring de novo genetic alterations and increased heterogeneity via mechanisms that remain incompletely understood1. Here, through parallel analysis of human clinical samples, tumour xenograft and cell line models and murine model systems, we uncover an unanticipated mechanism of therapy-induced adaptation that fuels the evolution of drug resistance. Targeted therapy directed against EGFR and ALK oncoproteins in lung cancer induced adaptations favoring apolipoprotein B mRNA-editing enzyme, catalytic polypeptide (APOBEC)-mediated genome mutagenesis. In human oncogenic EGFR-driven and ALK-driven lung cancers and preclinical models, EGFR or ALK inhibitor treatment induced the expression and DNA mutagenic activity of APOBEC3B via therapy-mediated activation of NF-{kappa}B signaling. Moreover, targeted therapy also mediated downregulation of certain DNA repair enzymes such as UNG2, which normally counteracts APOBEC-catalyzed DNA deamination events. In mutant EGFR-driven lung cancer mouse models, APOBEC3B was detrimental to tumour initiation and yet advantageous to tumour progression during EGFR targeted therapy, consistent with TRACERx data demonstrating subclonal enrichment of APOBEC-mediated mutagenesis. This study reveals how cancers adapt and drive genetic diversity in response to targeted therapy and identifies APOBEC deaminases as future targets for eliciting more durable clinical benefit to targeted cancer therapy.

cancer biology↗

bioRxiv2019

Epidemiology of human culture: parietal rock art requires high population density

Demographic models of human cultural evolution have high explanatory potential but weak empirical support. Here we use a global dataset of rock art sites and climate and genetics-based estimates of ancient population densities to test a new model based on epidemiological principles. The model focuses on the process whereby a cultural innovation becomes endemic in a population. It predicts that this cannot occur unless population density exceeds a critical value. Analysis of the data, using a Bayesian statistical framework, shows that the model has stronger empirical support than a null model, where rock art detection rates and population density are independent, or a proportional model where detection is directly proportional to population density. Comparisons between results for different geographical areas and periods yield qualitatively similar results, supporting the robustness of the model. Re-analysis of the rock art data, using a second set of independent population estimates, yields similar results. We conclude that population density above a critical threshold is a necessary condition for the maintenance of rock art as a stable part of a populations cultural repertoire. Methods similar to those described can be used to test the model for other classes of archaeological artifact and to compare it against other models.

paleontology↗

bioRxiv2019

Ventral Pallidum is Essential for Cocaine Reinstatement After Voluntary Abstinence

Addiction is a chronic relapsing disorder, and during recovery many people experience several relapse events as they attempt to voluntarily abstain from drug. New preclinical relapse models have emerged which capture this common human experience of relapse after voluntary abstinence, and mounting evidence indicates that reinstatement of drug seeking after voluntary abstinence recruits neural circuits distinct from reinstatement following experimenter-imposed abstinence, or abstinence due to extinction training. Ventral pallidum (VP), a key limbic node involved in drug seeking, has well-established roles in conventional reinstatement models tested following extinction training, but it is unclear whether this region also participates in more translationally-relevant models of relapse. Here we show that chemogenetic inhibition of VP neurons strongly attenuates cocaine-, context-, and cue-induced reinstatement tested after voluntary, punishment-induced abstinence. This effect was strongest in the most compulsive, punishment-resistant rats, and reinstatement was associated with neural activity in anatomically-defined VP subregions. VP inhibition also attenuated the propensity of rats to display hesitations, a risk assessment behavior seen during punished drug taking that is likely due to concurrent approach and avoidance motivations. These results indicate that VP, unlike other connected limbic brain regions, is essential for reinstatement of drug seeking after voluntary abstinence. Since VP inhibition effects were strongest in the most compulsively cocaine-seeking individuals, this could indicate that VP plays a particularly important role in the most pathological, addiction-like behavior, making it an attractive target for future therapeutic interventions.

neuroscience↗