Biology subjects

James, M. H.

Publications and source records attributed to James, M. H..

12 recordsLinked to original sources

bioRxiv2025

Reducing astrocyte calcium in the nucleus accumbens core increases reward valuation

Astrocyte dysfunction within the nucleus accumbens (NAc) has been increasingly implicated in maladaptive reward processing and the development of addiction-like behaviors. In this study, we investigated how impairing astrocyte calcium signaling in the NAc core influences consummatory reward behaviors and reward valuation. Using a viral approach to express the human plasma membrane calcium ATPase (hPMCA) in NAc core astrocytes in male rats, we selectively reduced intracellular astrocyte calcium dynamics. Blunting astrocyte calcium signaling led to increased self-administration of both sucrose and cocaine on a low effort fixed-ratio schedule of reinforcement. Behavioral economic analysis revealed enhanced reward motivation and valuation in hPMCA-expressing rats as compared to controls. Notably, reduction of astrocyte calcium signaling did not alter cocaine-induced locomotor sensitization, indicating a dissociation between astrocytic regulation of reward valuation and other cocaine-related behaviors. Collectively, these results identify astrocyte calcium dynamics in the NAc core as a key constraint on motivational drive and reward valuation.

neuroscience↗

bioRxiv2022

The cognitive basis of intracranial self-stimulation of midbrain dopamine neurons

Recently there has been a reckoning in the dopamine field. This has suggested that the dopamine prediction error may function as a teaching signal, without endowing preceding events with value. We studied the cognitive basis of intracranial self-stimulation (ICSS), a setting where dopamine appears to be valuable. Physiological frequencies seen during reinforcement learning did not support robust ICSS or promote behavior that would indicate the stimulation was represented as a meaningful reward in a specific or general sense. This was despite demonstrating that this same physiologically-relevant signal could function as a teaching signal. However, supraphysiological frequencies supported robust ICSS where the stimulation was represented as a specific sensory event, which acted as a goal to motivate behavior. This demonstrates that dopamine neurons only support ICSS at supraphysiological frequencies, and in a manner that does not reflect our subjective experience with endogenous firing of dopamine neurons during reinforcement learning. One sentence summaryDopamine neurons only support ICSS at supraphysiological frequencies and in a manner not reflecting dopamines role in learning.

neuroscience↗

bioRxiv2021

Rat anterior cingulate cortex continuously signals decision variables in a patchforaging task

In patch foraging tasks, animals must decide whether to remain with a depleting resource or to leave it in search of a potentially better source of reward. In such tasks, animals consistently follow the general predictions of optimal foraging theory (the Marginal Value Theorem; MVT): to leave a patch when the reward rate in the current patch depletes to the average reward rate across patches. Prior studies implicate an important role for the anterior cingulate cortex (ACC) in foraging decisions based on MVT: within single trials, ACC activity increases immediately preceding foraging decisions, and across trials, these dynamics are modulated as the value of staying in the patch depletes to the average reward rate. Here, we test whether these activity patterns reflect dynamic encoding of decision-variables and whether these signals are directly involved in decision-making. We developed a leaky accumulator model based on the MVT that generates estimates of decision variables within and across trials, and tested model predictions against ACC activity recorded from rats performing a patch foraging task. Model predicted changes in MVT decision variables closely matched rat ACC activity. Next, we pharmacologically inactivated ACC to test the contribution of these signals to decision-making. ACC inactivation had a profound effect on rats foraging decisions and response times yet rats still followed the MVT decision rule. These findings suggest that the ACC encodes foraging-related variables for reasons unrelated to patch-leaving decisions.

neuroscience↗

bioRxiv2021

Chemogenetic stimulation of a retinal circuit activates brain noradrenergic neurons, prevents apoptosis, and suppresses depression-like behaviors

A chronically dysregulated locus coeruleus (LC) system gives rise to mood disorders. In particular, prolonged LC hyperactivity often underlies stress disorders, whereas chronically reduced function often underlies symptoms of depression. Owing to its location deep in the brainstem, LC is difficult to access which limits translational approaches that involve manipulating these neurons. Here, we circumvent this problem by utilizing the retina as a chemogenetic target for commandeering a multsynaptic circuit to LC. We show that activation of this pathway can prevent depression-like behavior and associated pathology of the LC-noradrenergic (NA) system caused by light deprivation. Additionally, we show that melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs) are the likely cell type responsible for initiating activity in this pathway. By capitalizing on this ocular route of designer receptor delivery, we demonstrate a novel, minimally-invasive method for manipulating this deep-brain circuit that is relevant to a wide array of neuropsychiatric disorders.

neuroscience↗

bioRxiv2020

The dual orexin/hypocretin receptor antagonist suvorexant reduces addiction-like behaviors for the opioid fentanyl

The orexin (hypocretin) system is critical for motivated seeking of all drugs of abuse, including opioids. In 2019, the National Institute on Drug Addiction (NIDA) identified the orexin system as a high priority target mechanism for novel pharmacological therapies to treat opioid use disorder (OUD). Suvorexant (Belsomra) is a dual orexin receptor 1/orexin receptor 2 (OxR1/OxR2) antagonist that is FDA-approved for the treatment of insomnia, and thus has the potential to be readily repurposed for the treatment of OUD. However, studies have yet to test the therapeutic potential of suvorexant with respect to reducing opioid-related behaviors. Accordingly, here we investigated the efficacy of suvorexant in reducing several addiction-relevant behaviors in fentanyl self-administrating rats. In rats with limited drug experience, suvorexant decreased motivation for fentanyl on a behavioral economics (BE) task. This effect was greatest in rats with the highest motivation for fentanyl. Suvorexant was even more effective at decreasing motivation for fentanyl following induction of a more robust addiction phenotype by intermittent access (IntA) self-administration of the opioid. Suvorexant also attenuated punished responding for fentanyl and reduced cued reinstatement in IntA rats. Suvorexant did not affect general locomotor activity or natural reward seeking, indicating that at the doses used here, suvorexant can be used to reduce drug seeking with limited sedative or off-target effects. Together, these results highlight the therapeutic potential of suvorexant, particularly in individuals with the severe OUD.

neuroscience↗

bioRxiv2020

Intermittent self-administration of fentanyl induces a multifaceted addiction state associated with persistent changes in the orexin system.

The orexin (hypocretin) system plays a critical role in motivated drug-taking. Cocaine self-administration with the intermittent access (IntA) procedure produces a robust addiction-like state that is orexin-dependent. Here, we sought to determine the role of the orexin system in opioid addiction using IntA self-administration of fentanyl. Different groups of male rats were either given continuous access in 1h (short access; ShA), or 6h periods (long access, LgA), or IntA (5min of access separated by 25min of no-access) to fentanyl for 14 days. IntA produced a greater escalation of fentanyl intake, motivation for fentanyl on a behavioral economics task, persistent drug seeking during abstinence, and cued-induced reinstatement compared to rats given ShA or LgA. We found that addiction behaviors induced by IntA to fentanyl were reversed by the orexin-1 receptor antagonist SB-334867. IntA to fentanyl was also associated with a persistent increase in the number of orexin-expressing neurons. Together, results indicate that the IntA model is a useful tool in the study of opioid addiction, and that the orexin system is critical for the maintenance of addiction behaviors induced by IntA self-administration of fentanyl.

neuroscience↗

bioRxiv2019

The number of lateral hypothalamus orexin/hypocretin neurons contributes to individual differences in cocaine demand

Lateral hypothalamus (LH) orexin neuron signaling has been implicated in the motivation to seek and take drugs of abuse. The number of LH orexin neurons has been shown to vary with behavioral state and can be upregulated with exposure to drugs of abuse. We sought to determine if the number of LH orexin neurons related to individual differences in motivation (demand) for cocaine in our behavioral economics (BE) paradigm, and whether knockdown of these cells predicted changes in economic demand. We quantified LH orexin cell numbers in animals immediately following our BE paradigm, as well as BE-experienced animals after a two-week period of abstinence to relate the number of LH orexin cells to economic demand for cocaine. We also unilaterally knocked down LH orexin expression prior to BE with an orexin morpholino antisense to determine how reduced orexin numbers impacted cocaine demand. Animals with greater motivation for cocaine (lower demand elasticity) had more LH orexin neurons. Following a two-week abstinence from BE, the number of LH orexin neurons predicted economic demand for cocaine prior to abstinence. Reducing LH orexin cell numbers with antisense decreased motivation for cocaine (increased demand elasticity) without affecting baseline consumption. In addition, the number of spared LH orexin neurons after antisense treatment correlated with individual demand for cocaine. These studies point to a role for the endogenous number of LH orexin neurons in individual differences in motivation for cocaine.

neuroscience↗

bioRxiv2019

The Role of Orexin-1 Receptor Signaling in Demand for the Opioid Fentanyl

The orexin system is a potential treatment target for drug addiction. Orexin-1 receptor (OxR1) antagonism reduces demand for cocaine and remifentanil indicating that orexin-based therapies may reduce demand for many classes of abused drugs. However, pharmacokinetics vary greatly among opioids and it is unclear if OxR1 antagonism would reduce demand for all opioids, particularly ones with particularly high abuse liability. Here, we establish a behavioral economics (BE) procedure to assess the effects of OxR1 antagonism on demand for the highly abused opioid fentanyl. We also investigate the utility of our novel procedure in predicting OxR1 antagonism efficacy and relapse propensity. The OxR1 antagonist SB-334867 (SB) increased demand elasticity (; decreased motivation) for fentanyl without affecting preferred consumption of fentanyl at null cost (Qo). Baseline values predicted SB efficacy, such that SB was most effective at increasing demand elasticity in highly motivated rats. SB also attenuated cue-induced fentanyl seeking and baseline values predicted the amount of reinstatement behavior. These results highlight the promise of the orexin system as a treatment target for opioid addiction and emphasize the usefulness of BE procedures in the study of opioid abuse.

animal behavior and cognition↗

bioRxiv2018

The orexin-1 receptor antagonist SB-334867 reduces motivation, but not inhibitory control, in a rat stop signal task

There is considerable clinical interest in the neuropeptide orexin/hypocretin for its ability to regulate motivation and reward as well as arousal and wakefulness. For instance, antagonists for the orexin-1 receptor (OxR1) are thought to hold great promise for treating drug addiction and disorders associated with overeating, as these compounds repeatedly have been found to suppress seeking of various drugs of abuse as well as highly palatable foods in preclinical models. Given the hypothesized role of OxR1 signaling in cue-driven motivation, an outstanding question is whether pharmacologically blocking this receptor affects cognitive functioning. Response inhibition - the ability to cancel ongoing behavior - is one aspect of cognitive control that may be particularly relevant. Response inhibition deficits are commonly associated with a range of psychiatric disorders and neurological diseases, including substance use disorders and obesity. Moreover, OxR1 signaling recently has been implicated in waiting impulsivity, another aspect of inhibitory control. Here, we investigated the effects of the OxR1 antagonist SB-334867 on response inhibition in a rat version of the stop signal reaction time task. Results show that acutely blocking OxR1 had minimal effects on response inhibition or attentional functioning. In contrast, this manipulation reduced motivation to perform the task and earn food rewards. These results add to the growing body of literature implicating OxR1 in the regulation of motivation and suggest that effects of pharmacological compounds such as SB-334867 on drug seeking behavior are not related to effects on response inhibition.\n\nHighlightsO_LIOrexin-1 receptor antagonists hold great promise for treatment of drug addiction\nC_LIO_LIThese compounds are thought to reduce motivation for drug seeking\nC_LIO_LILess is known about effects of orexin-1 receptor blockade on cognitive functioning\nC_LIO_LIWe tested the orexin-1 receptor antagonist SB-334867 in a rat stop signal task\nC_LIO_LISB-334867 reduced task motivation but had little effect on executive control as measured with response inhibition\nC_LI

neuroscience↗

bioRxiv2018

Activation of lateral hypothalamic group III mGluRs suppresses drug-seeking following abstinence and cocaine-associated increases in excitatory drive to orexin/hypocretin cells

The perifornical/lateral hypothalamic area (LHA) orexin (hypocretin) system is involved in drug-seeking behavior elicited by drug-associated stimuli. Cocaine exposure is associated with presynaptic plasticity at LHA orexin cells such that excitatory input to orexin cells is enhanced, both acutely and into withdrawal. These changes may augment orexin cell reactivity to drug-related cues during abstinence and contribute to relapse-like behavior. Studies in hypothalamic slices from drug-naive animals indicate that agonism of group III metabotropic glutamate receptors (mGluRs) reduces presynaptic glutamate release onto orexin cells. Therefore, we examined the group III mGluR system as a potential target to reduce orexin cell excitability in-vivo, and tested whether activating these receptors could normalize orexin cell activity following cocaine and reduce cocaine-seeking elicited by drug-associated stimuli during abstinence. First, we verified that group III mGluRs regulate orexin cell activity in vivo by showing that intra-LHA infusions of the selective agonist L-(+)-2-Amino-4-phosphonobutyric acid (L-AP4) reduces Fos expression in orexin cells following 24h food deprivation. Next, we extended these findings to show that intra-LHA L-AP4 infusions reduced discriminative stimulus-driven cocaine-seeking following withdrawal. L-AP4 had no effect on general motor activity of sucrose self-administration. Finally, using whole-cell patch clamp recordings from identified orexin cells in orexin-GFP transgenic mice, we show that enhanced presynaptic drive to orexin cells persists for up to 14d into withdrawal and that this plasticity is normalized by L-AP4. L-AP4 had no effect on measures of postsynaptic plasticity in cocaine-exposed animals. Together, these data indicate that agonism of LHA group III mGluRs reduces orexin cell activity in-vivo and is an effective strategy to suppress cocaine-seeking behavior following withdrawal. These effects are likely mediated, at least in part, by normalization of presynaptic plasticity at orexin cells that occurs as a result of cocaine exposure.

neuroscience↗

bioRxiv2018

Orexin-1 receptor signaling in ventral pallidum mediates demand for the opioid remifentanil

Signaling at the orexin-1 receptor (Ox1R) is important for motivation for various drugs of abuse. Recently, our laboratory showed that systemic blockade of Ox1Rs decreased motivation for the potent and short-acting opioid remifentanil (Porter-Stransky et al, 2017). However, the central sites through which orexin acts to mediate motivation for opioids are not known. Here, we investigated ventral pallidum (VP) as a potential site of orexin action, as VP is a known mediator of opioid reward and is densely innervated by orexin-immunoreactive fibers. We used a within-session behavioral economics (BE) paradigm in which remifentanil price (responses/{micro}g iv remifentanil) was sequentially increased throughout the session. Rats were implanted with bilateral cannulae into VP, through which microinjections of SB334867 (SB), and orexin 1 receptor (Ox1R) antagonist, were given prior to BE testing. Rats were then extinguished and subjected to cue-induced reinstatement following intra-VP SB microinjection. We found that inhibition of Ox1R signaling in VP reduced both motivation (increased demand elasticity) for remifentanil and cued reinstatement of extinguished remifentanil-seeking without affecting baseline consumption or general locomotor activity. These effects were specific to the VP, as control injections of SB immediately dorsal to VP did not affect remifentanil-seeking. Together, these findings indicate a selective role of Ox1R signaling in VP in motivation and relapse for the opioid remifentanil.

animal behavior and cognition↗

bioRxiv2018

Demand elasticity predicts addiction endophenotypes and the therapeutic efficacy of an orexin/hypocretin-1 receptor antagonist in rats

Behavioral economics is a powerful, translational approach for measuring drug demand in both humans and animals. Here, we asked if demand for cocaine in rats with limited drug experience could be used to identify individuals most at risk of expressing an addiction phenotype following either long (LgA) or intermittent (IntA) access self-administration schedules, both of which model the transition to uncontrolled drug seeking. Moreover, because the orexin-1 receptor antagonist SB-334867 (SB) is particularly effective at reducing drug-seeking in highly motivated individuals, we asked whether demand measured after prolonged drug experience could predict SB efficacy. Demand elasticity () measured immediately following acquisition of cocaine self-administration ( baseline ) was positively correlated with assessed after 2w of LgA or IntA. Baseline also predicted the magnitude of compulsive responding for cocaine, drug seeking in initial abstinence, and cued reinstatement following LgA, IntA or standard short access (ShA). When demand was measured after LgA, IntA or ShA, predicted the same addiction endophenotypes predicted by baseline , as well as primed reinstatement and the emergence of negative emotional mood behavior following abstinence. Post-LgA/IntA/ShA also predicted the efficacy of SB, such that high demand rats showed greater reductions in motivation for cocaine following SB (10 and 30mg/kg) compared to low demand rats. Together, these findings indicate that might serve as a behavioral biomarker to predict individuals most likely to progress from controlled to uncontrolled drug use, and to identify individuals most likely to benefit from orexin-based therapies for the treatment of addiction.

neuroscience↗