Biology subjects

Martin, D. A.

Publications and source records attributed to Martin, D. A..

11 recordsLinked to original sources

bioRxiv2026

MR-Guided Focused Ultrasound Neuromodulation of Nucleus Accumbens to Attenuate Oral Fentanyl Motivation in A Self-Administration Rat Model

Introduction: Transcranial low-intensity focused ultrasound (LIFU) is being explored as a non-invasive approach for neuromodulation to treat opioid use disorder (OUD). Methods: We evaluated MR-guided focused ultrasound, with LIFU, targeting nucleus accumbens (MRgLIFU-NAc) bilaterally, using MR-acoustic radiation force-imaging (MR-ARFI) to ensure accurate targeting and adjust for FUS intensity delivered at the target. Male and female rats were trained to self-administer fentanyl/sucrose (70ug/ml fentanyl citrate in 5% sucrose) or 5% sucrose alone. Three cohorts of rats (total n=76) were evaluated on progressive ratio (PR) responding for oral fentanyl/sucrose at either 4 or 24 hours post-MRgLIFU-NAc. Animals in the first two cohorts received repeated rounds of LIFU or sham (anesthesia-duration matched). In cohort 3, we used a counterbalanced within-subjects design in which rats received both LIFU and sham one week apart. Results: Reducing sucrose concentrations decreased responding for sucrose alone more than for fentanyl/sucrose, demonstrating a role for fentanyl in the reinforcing properties of fentanyl/sucrose. Across three sonication schemes, MRgLIFU-NAc did not attenuate PR performance for oral fentanyl/sucrose at 4 or 24-hours post-LIFU relative to controls. Adjusting LIFU intensity with MR-ARFI did not correlate with changes in PR from baseline. We confirmed that NAc is the correct target by bilateral inactivation of NAc with muscimol/baclofen mixture (50 + 50 ng/side), which reduced PR responding for fentanyl/sucrose. Conclusion: The three sets of LIFU parameters, with repeated MRgLIFU-NAc sessions, did not produce detectable changes in oral fentanyl/sucrose motivation. Further studies are required to determine effective LIFU parameters needed to reduce NAc-dependent fentanyl motivation.

neuroscience↗

bioRxiv2026

Opposing reward-epoch population coding in anterior insular cortex dissociates sign- and goal-tracking despite equivalent conditioned responding

When Pavlovian lever cues predict reward, rats diverge in how they express learned associations: sign-tracking (ST) rats approach and engage the cue with greater persistence, while goal-tracking (GT) rats approach the reward site and are more consistently outcome-sensitive. The anterior insular cortex (aIC) and its interactions with amygdala and striatal regions are differentially recruited across phenotypes, implicating aIC as a node where associative strategy diverges at the circuit level. To characterize this neural divergence independent of differences in conditioned responding, we recorded single-unit aIC activity in ST and GT rats performing an odor-guided sucrose discrimination task with equivalent approach behavior. At the population level, GT aIC was dominated by task-excited neurons that drove sucrose discrimination, while ST aIC carried a greater proportion of task-inhibited neurons whose suppression carried the dominant discrimination signal, a dissociation specific to the reward epoch. During cue sampling, the balance of excited and inhibited neurons did not differ between phenotypes, but temporal structure diverged: ST cue-excited neurons showed transient CS-onset responses without sustained discrimination, while GT cue-excited neurons maintained sustained CS+/CS- discrimination into the reward epoch. ST cue-period firing predicted post-cue approach latency, with stronger responses associated with slower goal approach, a relationship absent in GT. The majority of optogenetically identified aIC projection neurons targeting basolateral amygdala and nucleus accumbens were cue-inhibited. These findings reveal that individual differences in associative strategy are encoded in the organizational structure of aIC population activity, positioning aIC as a site where motivational strategy is translated into distinct outputs.

neuroscience↗

bioRxiv2024

The psychedelic, DOI, increases dopamine release in nucleus accumbens to predictable rewards and reward cues

Psychedelics produce lasting therapeutic responses in neuropsychiatric diseases suggesting they may disrupt entrenched associations and catalyze learning. Here, we examine psychedelic effects on dopamine signaling in the nucleus accumbens (NAc) core, a region extensively linked to reward learning, motivation, and drug-seeking. We measure phasic dopamine transients following acute psychedelic administration during well learned Pavlovian tasks in which sequential cues predict rewards. We find that the psychedelic 5-HT2A/2C agonist, DOI, increases dopamine signaling to rewards and proximal reward cues but not to the distal cues that predict these events. We determine that the elevated dopamine produced by psychedelics to reward cues occurs independently of psychedelic-induced changes in reward value. The increased dopamine associated with predictable reward cues supports psychedelic-induced increases in prediction error signaling. These findings lay a foundation for developing psychedelic strategies aimed at engaging error-driven learning mechanisms to disrupt entrenched associations or produce new associations.

neuroscience↗

bioRxiv2024

Stand structure as the proximate driver of endemic biodiversity and ecosystem functions in tropical mosaic landscapes

Transformation of forests into agricultural lands threatens biodiversity and ecosystem functions globally. In the biodiversity hotspot Madagascar, key ecosystem functions along with highly endemic flora and fauna are under threat. Comprehensive studies identifying proximate drivers are lacking, with no studies accounting for endemic species richness across multiple taxa. We assess how plot-scale stand structural attributes (basal area, leaf area index, diameter diversity, and tree species richness) and landscape-scale forest cover affect biodiversity (species richness of butterflies, ants, birds, amphibians, reptiles, herbaceous plants, and multidiversity) and ecosystem functions (soil organic carbon, predation rate, acoustic diversity index, and multifunctionality) in the tropical mosaic landscape of northeastern Madagascar. Across a prevalent land-use gradient in the region, we sampled five woody land-use types: old-growth forest, forest fragment, woody fallow, forest-derived and fallow-derived vanilla agroforests. Complexly structured stands with a larger basal area and higher tree species richness promoted greater endemic multidiversity and certain ecosystem functions. Landscape-scale forest cover significantly favored, particularly, endemic bird species richness. Our models explained 70% of the variance in endemic multidiversity, 26% in multidiversity, and 43% in multifunctionality. Significant effects directions of our predictors differed between taxa but were univocally positive for endemic species richness. Our findings highlight that a simplified stand structure, resulting from land-use change, substantially reduces endemic biodiversity and ecosystem functions in this historically forested region. Conservation actions should aim at maintaining complex stand structure in forests and agroforests, while restoration interventions should focus on re-building such structures.

ecology↗

bioRxiv2022

Decreased ventral tegmental area CB1R signaling reduces sign-tracking and shifts cue-outcome dynamics in rat nucleus accumbens

Sign-tracking rats show enhanced cue sensitivity before drug experience that predicts greater discrete cue-induced drug-seeking compared to goal-tracking or intermediate-rats. Cue-evoked dopamine in the nucleus Accumbens (NAc) is a neurobiological signature of sign-tracking behaviors. Here, we examine a critical regulator of the dopamine system; endocannabinoids, which bind the cannabinoid receptor-1 (CB1R) in the Ventral Tegmental Area (VTA) to control cue-evoked striatal dopamine levels. We use cell-type specific optogenetics, intra-VTA pharmacology and fiber photometry to test the hypothesis that VTA CB1R receptor signaling regulates NAc dopamine levels to control sign-tracking. We trained rats in a Pavlovian lever autoshaping task (PLA) to determine their tracking groups before testing the effect of VTA[->]NAc dopamine inhibition. We found this circuit is critical for mediating the vigor of the ST response. Upstream of this circuit, intra-VTA infusions of rimonabant, a CB1R inverse agonist, during PLA decrease lever and increase foodcup approach in sign-trackers. Using fiber photometry to measure fluorescent signals from dopamine sensor, GRABDA, we tested the effects of intra-VTA rimonabant on NAc dopamine dynamics during autoshaping. We found that intra-VTA rimonabant decreased sign-tracking behaviors, which was associated with increases NAc shell, but not core, dopamine levels during reward delivery (US). We also observed a relationship between cue (CS)-evoked NAc dopamine activity and rigidity of behavior between rimonabant treatment sessions. Our results suggest that CB1R signaling in the VTA influences the balance between the CS- and US-evoked dopamine responses in the NAc and biases behavioral responding to cues in sign-tracking rats. SIGNIFICANCE STATEMENTSubstance Use Disorder is a chronically relapsing neurobiological disorder that affects a subset of individuals that engage in drug use. Recent research suggests that there are individual behavioral and neurobiological differences prior to drug experience that predict addiction and relapse vulnerabilities. Here, we investigate how midbrain endocannabinoids regulate a brain pathway that is exclusively involved in driving cue-motivated behaviors of sign-tracking rats. This work contributes to our mechanistic understanding of individual vulnerabilities to cue-triggered natural reward seeking that have relevance for drug motivated behaviors.

neuroscience↗

bioRxiv2022

Dopamine in the Dorsal Bed Nucleus of Stria Terminalis signals Pavlovian sign-tracking and reward violations

Midbrain and striatal dopamine signals have been extremely well characterized over the past several decades, yet novel dopamine signals and functions in reward learning and motivation continue to emerge. A similar characterization of real-time sub-second dopamine signals in areas outside of the striatum has been limited. Recent advances in fluorescent sensor technology and fiber photometry permit measurement of dopamine binding correlates, which can divulge basic functions of dopamine signaling in non-striatal dopamine terminal regions, like the dorsal bed nucleus of the stria terminalis (dBNST). Here, we record GRABDA signals in the dBNST during a Pavlovian lever autoshaping task. We observe greater Pavlovian cue-evoked dBNST GRABDA signals in sign-tracking (ST) compared to goal-tracking/intermediate (GT/INT) rats and the magnitude of cue-evoked dBNST GRABDA signals decrease immediately following reinforcer-specific satiety. When we deliver unexpected reward or omit expected reward, we find that dBNST dopamine signals encode bidirectional reward prediction errors in GT/INT rats, but only positive prediction errors in ST rats. Since sign- and goal-tracking approach strategies are associated with distinct drug relapse vulnerabilities, we examined the effects of experimenter-administered fentanyl on dBNST dopamine associative encoding. Systemic fentanyl injections do not disrupt dBNST cue discrimination but generally potentiate dBNST dopamine signals. These results reveal multiple dBNST dopamine correlates of learning and motivation that depend on the Pavlovian approach strategy employed.

neuroscience↗

bioRxiv2022

Conserved reward-mediated, reinforcement-learning mechanisms in Pavlovian and instrumental tasks

Model-free and model-based computations are argued to distinctly update action values that guide decision-making processes. It is not known, however, if these model-free and model-based reinforcement learning mechanisms recruited in operationally based, instrumental tasks parallel those engaged by Pavlovian based behavioral procedures. Recently, computational work has suggested that individual differences in the attribution of incentive salience to reward predictive cues, i.e., sign- and goal-tracking behaviors, are also governed by variations in model-free and model-based value representations that guide behavior. Moreover, it is not appreciated if these systems that are characterized computationally using model-free and model-based algorithms are conserved across tasks for individual animals. In the current study, we used a within- subject design to assess sign-tracking and goal-tracking behaviors using a Pavlovian conditioned approach task, and, then characterized behavior using an instrumental multi-stage decision-making (MSDM) task in rats. We hypothesized that both Pavlovian and instrumental learning processes may be driven by common reinforcement-learning mechanisms. Our data confirm that sign-tracking behavior was associated with greater reward-mediated, model-free reinforcement learning and that it was also linked to model-free reinforcement learning in the MSDM task. Computational analyses revealed that Pavlovian model-free updating was correlated with model-free reinforcement learning in the MSDM task. These data provide key insights into the computational mechanisms mediating associative learning that could have important implications for normal and abnormal states. Significance StatementModel-free and model-based computations that guide instrumental, decision-making processes may also be recruited in Pavlovian based behavioral procedures. Here, we used a within-subject design to test the hypothesis that both Pavlovian and instrumental learning processes were driven by common reinforcement-learning mechanisms. Sign- tracking and goal-tracking behaviors were assessed in rats using a Pavlovian conditioned approach task, and, then instrumental behavior characterized using a multi- stage decision-making (MSDM) task. We report that sign-tracking behavior was associated with greater model-free, but not model-based, learning in the MSDM task. These data suggest that Pavlovian and instrumental behaviors are driven by conserved reinforcement-learning mechanisms.

animal behavior and cognition↗

bioRxiv2022

Fentanyl reinstatement to discriminative cues after conflict in sign- and goal-tracking rats

RationaleDiscriminative stimuli (DS) are cues that predict reward availability. DS are resistant to extinction and motivate drug seeking even after long periods of abstinence. Previous studies have demonstrated that sign tracking (ST) and goal tracking (GT) individual differences in Pavlovian approach to food cues predict distinct vulnerabilities to CS and DS reinstatement of cocaine seeking, respectively. Compared to goal-trackers, sign-trackers show heightened CS relapse even after electric barrier induced abstinence. We do not know whether DS relapse persists after electric barrier induced abstinence, or whether tracking-related relapse vulnerabilities generalize to models of opioid relapse. ObjectivesWe sought to determine if DS-induced reinstatement of fentanyl seeking persists in the presence of reduced adverse consequences after electric barrier-induced abstinence. We also aimed to determine whether tracking differences predict the magnitude of DS-induced reinstatement of fentanyl seeking after electric barrier-induced abstinence. MethodsFirst we used Pavlovian lever autoshaping (PLA) training to determine sign-, goal- and intermediate tracking groups in male and female Sprague Dawley rats. We then trained rats in a DS model of intermittent fentanyl self-administration, and extinguished drug seeking by imposing an electric barrier of increasing intensity. We then measured the level of DS-induced reinstatement in the presence of a reduced electric barrier intensity. ResultsWe report that DS produce large increases in fentanyl seeking after electric barrier induced abstinence. Contrary to our expectations, the magnitude of the DS induced reinstatement effect was not related to tracking group. ConclusionsDiscriminative stimuli powerfully motivate opioid seeking, despite continued aversive consequences. Individual differences in Pavlovian approach do not predict the level of DS reinstatement to fentanyl seeking after conflict induced abstinence.

animal behavior and cognition↗

bioRxiv2021

Differential responses of amphibians and reptiles to land-use change in the biodiversity hotspot of north-eastern Madagascar

Large expanses of tropical rainforest have been converted into agricultural landscapes cultivated by smallholder farmers. This is also the case in north-eastern Madagascar; a region that retains significant proportions of forest cover despite slash-and-burn hill rice cultivation and vanilla agroforestry expansion. The region is also a global hotspot for herpetofauna diversity, but how amphibians and reptiles are affected by land-use change remains largely unknown. Using a space-for-time study design, we compared species diversity and community composition across seven prevalent land uses: unburned (old-growth forest, forest fragment, and forest-derived vanilla agroforest) and burned (fallow-derived vanilla agroforest, woody fallow, and herbaceous fallow) land-use types, and rice paddy. We conducted six comprehensive, time-standardized searches across at least ten replicates of each land-use type and applied genetic barcoding to confirm species identification. We documented an exceptional diversity of herpetofauna (119 species; 91% endemic). Plot-level amphibian species richness was significantly higher in old-growth forest than in all other land-use types. Plot-level reptile species richness was significantly higher in unburned land-use types compared to burned land-use types. For both amphibians and reptiles, the less-disturbed land-use types showed more uneven communities and the species composition in old-growth forest differed significantly from all other land-use types. Amphibians had higher forest dependency (38% of species occurred exclusively in old-growth forest) than reptiles (26%). Our analyses thus revealed that the two groups respond differently to land-use change: we found less pronounced losses of reptile species richness especially in unburned agricultural habitats, suggesting that reptiles are less susceptible to land-use change than amphibians, possibly due to their ability to cope with hotter and drier microclimates. Overall, old-growth forest harboured a unique diversity, but some species also thrived in vanilla agroforestry systems, especially if these were forest-derived. This highlights the importance of conserving old-growth forests and non-burned land-use types within agricultural landscapes.

ecology↗

bioRxiv2020

Trial-by-trial variability in cortical responses exhibits scaling in spatial correlations predicted from critical dynamics

Simple sensory stimuli or motor outputs engage large populations of neurons in the mammalian cortex. When stimuli or outputs repeat, the robust population response contrasts with fluctuating responses of individual neurons, known as trial-by-trial variability. To understand this apparent discrepancy, a detailed identification of the underlying spatiotemporal correlations is required. Here, we analyze spatial correlations in the instantaneous fluctuations between neurons relative to the neuronal population. Using 2-photon imaging of visual and auditory responses in primary cortices of awake mice, we show that these correlations grow linearly with the size of the observed cortical area. We extend these observations to the cortical mesoscale by analyzing local field potentials in behaving nonhuman primates. In network simulations, we demonstrate this linear growth in spatial correlation to emerge at criticality. Our findings suggest that trial-by-trial variability is a signature of critical dynamics in cortex maintaining robust, long-range spatial correlations among neurons.

neuroscience↗

bioRxiv2018

Meta-analysis challenges a textbook example of status signalling: evidence for publication bias

The status signalling hypothesis aims to explain conspecific variation in ornamentation by suggesting that some ornaments signal dominance status. Here, we use multilevel meta-analytic models to challenge the textbook example of this hypothesis, the black bib of house sparrows (Passer domesticus). We conducted a systematic review, and obtained raw data from published and unpublished studies to test whether dominance rank is positively associated with bib size across studies. Contrary to previous studies, our meta-analysis did not support this prediction. Furthermore, we found several biases in the literature that further question the support available for the status signalling hypothesis. First, the overall effect size of unpublished studies was zero, compared to the medium effect size detected in published studies. Second, the effect sizes of published studies decreased over time, and recently published effects were, on average, no longer distinguishable from zero. We discuss several explanations including pleiotropic, population- and context-dependent effects. Our findings call for reconsidering this established textbook example in evolutionary and behavioural ecology, raise important concerns about the validity of the current scientific publishing culture, and should stimulate renewed interest in understanding within-species variation in ornamental traits.

evolutionary biology↗