Biology subjects

Panayi, M. C.

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

10 recordsLinked to original sources

bioRxiv2023

The selective D3-Receptor antagonist VK4-116 effectively treats behavioral inflexibility in rats caused by self-administration and withdrawal from cocaine

Chronic psychostimulant use can cause long lasting changes to neural and cognitive function that persist even after long periods of abstinence. As cocaine users transition from drug use to abstinence, a parallel transition from hyperactivity to hypoactivity has been found in orbitofrontal-striatal glucose metabolism, and striatal D2/D3 receptor activity. Targeting these changes pharmacologically, using highly selective dopamine D3 receptor (D3R) antagonists and partial agonists, has shown significant promise in reducing drug-taking, and attenuating relapse in animal models of cocaine and opioid use disorder. However, much less attention has been focused on treating inflexible and potentially maladaptive non-drug behaviors following chronic psychostimulant use. Here we tested the selective D3R antagonist VK4-116 as a treatment for the long-term behavioral inflexibility in abstinent male and female rats with a prior history of chronic cocaine use. Rats were first trained to self-administer cocaine (0.75 mg/kg/reinforcer) or a sucrose liquid (10%, .04 mL/reinforcer) for 2 weeks (FR1 schedule, max 60 reinforcers in 3 hrs/ day), followed by 4 weeks of abstinence. Cognitive and behavioral flexibilities were then assessed using a sensory preconditioning (SPC) learning paradigm. Rats were given an VK4-116 (15 mg/kg, i.p.) or vehicle 30 mins prior to each SPC training session, thus creating four drug-treatment groups: sucrose-vehicle, sucrose-VK4-116, cocaine-vehicle, cocaine-VK4-116. The control groups (sucrose-vehicle, sucrose-VK4-116) demonstrated significant evidence of flexible SPC behavior, whereas cocaine use (cocaine-vehicle) disrupted SPC behavior. Remarkably, the D3R antagonist VK4-116 mitigated this cocaine deficit in the cocaine-VK4-116 group, demonstrating flexible SPC to levels comparable to the control groups. These preclinical findings demonstrate that highly selective dopamine D3R antagonists, particularly VK4-116, show significant promise as a pharmacological treatment for the long-term negative behavioral consequences of cocaine use disorder.

neuroscience↗

bioRxiv2023

Cocaine Seeking And Taking Are Oppositely Regulated By Dopamine

In some individuals, drug-associated cues subsume potent control of behavior, such as the elicitation of drug craving1-3 and automatized drug use4. The intensity of this cue reactivity is highly predictive of relapse and other clinical outcomes in substance use disorders5, 6. It has been postulated that this cue reactivity is driven by augmentation of dopamine release over the course of chronic drug use7. Here we carried out longitudinal recording and manipulation of cue-evoked dopamine signaling across phases of substance-use related behavior in rats. We observed a subset of individuals that exhibited increased cue reactivity and escalated drug consumption, two cardinal features of substance use disorders. In these individuals, cue-evoked phasic dopamine release underwent diametrically opposed changes in amplitude, determined by the context in which the cue is presented. Dopamine evoked by non-contingent cue presentation increased over drug use, producing greater cue reactivity; whereas dopamine evoked by contingent cue presentation decreased over drug use, producing escalation of drug consumption. Therefore, despite being in opposite directions, these dopamine trajectories each promote core symptoms of substance use disorders.

neuroscience↗

bioRxiv2022

Orbitofrontal Cortex is necessary for the behavioural expression, but not learning, of Pavlovian conditioned inhibition

Orbitofrontal cortex (OFC) lesions cause deficits in flexible behavioural control, most notably response inhibition and has historically been linked to theories of response inhibition. This general inhibition hypothesis of OFC function has since been rejected by evidence that inhibitory behavioural control can be expressed following OFC damage, however the functional role of the OFC in the explicit learning of conditioned inhibition remains untested. Here we test whether muscimol disruption of OFC function during the learning stage of a Pavlovian conditioned inhibition procedure disrupted the learning of conditioned inhibitory associations. Muscimol abolished Inhibitory behavioural control during the learning phase, however learning about the conditioned inhibitor was intact when tested drug free in subsequent summation and retardation tests of conditioned inhibition. Muscimol also significantly impaired acquisition to control cues whose cue-outcome relationship did not change. In a second experiment, conditioned inhibition was found not to play a significant role in cue extinction (non-reinforcement), an effect that was disrupted by intra-OFC infusion of muscimol. These results confirm that the OFC is not functionally necessary for the learning of inhibitory associations but is critical to both the enhancement and suppression of responding when environmental contingencies change.

animal behavior and cognition↗

bioRxiv2021

Glutamatergic dysfunction leads to a hyper-dopaminergic phenotype through deficits in short-term habituation: a mechanism for aberrant salience.

Psychosis in disorders like schizophrenia is commonly associated with aberrant salience and elevated striatal dopamine. However, the underlying cause(s) of this hyper-dopaminergic state remain elusive. Various lines of evidence point to glutamatergic dysfunction and impairments in synaptic plasticity in the aetiology of schizophrenia, including deficits associated with the GluA1 AMPAR subunit. GluA1 knockout (Gria1-/-) mice provide a model of impaired synaptic plasticity in schizophrenia and exhibit a selective deficit in a form of short-term memory which underlies short-term habituation. As such, these mice are unable to reduce attention to recently presented stimuli. In this study we used fast-scan cyclic voltammetry to measure phasic dopamine responses in the nucleus accumbens of Gria1-/- mice to determine whether this behavioral phenotype might be a key driver of a hyper-dopaminergic state. There was no effect of GluA1 deletion on electrically-evoked dopamine responses in anaesthetized mice, demonstrating normal endogenous release properties of dopamine neurons in Gria1-/- mice. Furthermore, dopamine signals were initially similar in Gria1-/- mice compared to controls in response to both sucrose rewards and neutral light stimuli. They were also equally sensitive to changes in the magnitude of delivered rewards. In contrast, however, these stimulus-evoked dopamine signals failed to habituate with repeated presentations in Gria1-/- mice, resulting in a task-relevant, hyper-dopaminergic phenotype. Thus, here we show that GluA1 dysfunction, resulting in impaired short-term habituation, is a key driver of enhanced striatal dopamine responses, which may be an important contributor to aberrant salience and psychosis in psychiatric disorders like schizophrenia.

neuroscience↗

bioRxiv2021

Retrosplenial cortex is necessary for spatial and non-spatial latent learning in mice

Latent learning occurs when associations are formed between stimuli in the absence of explicit reinforcement. Traditionally, latent learning in rodents has been associated with the creation internal models of space. However, increasing evidence points to roles of internal models also in non-spatial decision making. Whether the same brain structures and processes support the creation of spatially-anchored or non-spatial internal models via latent learning, is an open question. To address this question, we developed a novel operant box task that allows to test spatial and non-spatial versions of a flavour-based sensory preconditioning paradigm. We probed the role of the retrosplenial cortex, a brain area associated with spatial cognition and subjective value representation, in this task using precise, closed-loop optogenetic silencing during different task phases. We show that the retrosplenial cortex is necessary for both spatial and non-spatial latent learning in mice. We further demonstrate that the requirement of retrosplenial cortex is limited to the preconditioning phase of the task. Our results provide insight into the specific role of the retrosplenial cortex in latent learning, demonstrate that latent learning plays a general part in the creation of internal models, independent of spatial anchors, and provide a novel avenue for studying model-based decision making.

neuroscience↗

bioRxiv2021

Nucleus accumbens D1-receptors regulate and focus transitions to reward-seeking action

While it is well established that dopamine transmission is integral in mediating the influence of reward expectations on reward-seeking actions, the precise causal role of dopamine transmission in moment-to-moment cue-driven behavioural control remains contentious. This is a particular issue in situations where it is necessary to refrain from responding to achieve a beneficial outcome. To examine this, we manipulated dopamine transmission pharmacologically as rats performed a Go/No-Go task that required them to either make or withhold action to gain either a small or large reward. Stimulation of D1Rs, both globally and locally in the nucleus accumbens core (NAcC) region consistently disrupted No-Go performance, potentiating inappropriate responses that clustered strongly just after cue presentation. D1R blockade did not, however, improve rats ability to withhold responses, but instead primarily disrupted performance on Go trials. While global D1R blockade caused a general reduction of invigoration of reward seeking actions, intra-NAcC administration of the D1R antagonist by contrast increased the likelihood that Go trial performance was in an "unfocused" state. Such a state was characterised, both on and off drug, by a reduction in the precision and speed of responding even though the appropriate action sequence was often executed. These findings suggests that the balance of activity at NAcC D1Rs plays a key role in enabling the rapid activation of a focused, reward-seeking state to enable animals to efficiently and accurately achieve their goal.

neuroscience↗

bioRxiv2021

Intraneuronal chloride levels encode tiredness in cortex

Continuous periods of wakefulness are associated with reduced performance levels due to the build-up of sleep pressure in active regions of the brain. These effects manifest as use-dependent changes in cortical network activity and the mechanisms underlying these changes represent targets for overcoming the cognitive effects of tiredness. Here we reveal a central role for intraneuronal chloride levels, which increase in a use-dependent manner during waking, and reduce the strength of local synaptic inhibition in mouse cortex. Activity-dependent increases in chloride account for spatial and temporal features of sleep pressure, they underlie cortical network oscillations in the sleep-deprived state, and targeting chloride regulation in cortex can rescue performance levels when tired. These findings provide a missing link between sleep-wake history, synaptic transmission and cortical dynamics. One-Sentence SummaryThe effects of sleep pressure on cortical function are caused by use-dependent changes in chloride-mediated synaptic inhibition.

neuroscience↗

bioRxiv2020

The role of the rodent lateral orbitofrontal cortex in simple Pavlovian cue-outcome learning depends on training experience

The orbitofrontal cortex (OFC) is a critical structure in the flexible control of value-based behaviours. OFC dysfunction is typically only detected when task or environmental contingencies change, against a backdrop of apparently intact initial acquisition and behaviour. While intact acquisition following OFC lesions in simple Pavlovian cue-outcome conditioning is often predicted by models of OFC function, this predicted null effect has not been thoroughly investigated. Here we test the effects of lesions and temporary muscimol inactivation of the rodent lateral OFC on the acquisition of a simple single cue-outcome relationship. Surprisingly, pre-training lesions significantly enhanced acquisition after over-training whereas post-training lesions and inactivation significantly impaired acquisition. This impaired acquisition to the cue reflects a disruption of behavioural control and not learning since the cue could also act as an effective blocking stimulus in an associative blocking procedure. These findings suggest that even simple cue-outcome representations acquired in the absence of OFC function are impoverished. Therefore, while OFC function is often associated with flexible behavioural control in complex environments, it is also involved in very simple Pavlovian acquisition where complex cue-outcome relationships are irrelevant to task performance.

neuroscience↗

bioRxiv2020

Organisation of afferents along the anterior-posterior and medial-lateral axes of the rat OFC

The orbitofrontal cortex (OFC) has been anatomically divided into a number of subregions along its medial-lateral axis, which behavioural research suggests have distinct functions. Recently, evidence has emerged suggesting functional diversity is also present along the anterior-posterior axis of the rodent OFC. However, the patterns of anatomical connections that underlie these differences have not been well characterised. Here, we use the retrograde tracer cholera toxin subunit B to simultaneously label the projections into the anterior lateral (ALO), posterior lateral (PLO), and posterior ventral (PVO) portions of the rat OFC. Our methodological approach allowed us to simultaneously compare the density and input patterns into these OFC subdivisions. We observed distinct and topographically organised projection patterns into ALO, PLO, and PVO from the mediodorsal and the submedius nuclei of the thalamus. We also observed different levels of connectivity strength into these OFC subdivisions from the amygdala, motor cortex, sensory cortices and medial prefrontal cortical structures, including medial OFC, infralimbic and prelimbic cortices. Interestingly, while labelling in some of these input regions revealed only a gradient in connectivity strength, other regions seem to project almost exclusively to specific OFC subdivisions. Moreover, differences in input patterns between ALO and PLO were as pronounced as those between PLO and PVO. Together, our results support the existence of distinct anatomical circuits within lateral OFC along its anterior-posterior axis.

neuroscience↗

bioRxiv2018

The rodent lateral orbitofrontal cortex represents expected Pavlovian outcome value but not identity

The orbitofrontal cortex (OFC) is critical for updating reward-directed behaviours flexibly when task contingencies are reversed, or when outcomes are devalued. We systematically examined the generality of these findings using lesions of the rodent lateral OFC (LO) in instrumental action-outcome, and Pavlovian cue-outcome, learning using specific satiety and taste aversion methods of outcome devaluation. LO lesions disrupted outcome devaluation in Pavlovian but not instrumental procedures. Furthermore, this effect was only observed when using taste-aversion devaluation. Using a specific Pavlovian-to-Instrumental transfer procedure, we established that LO is not necessary for the representation of specific outcome properties, but rather in using these properties to access the current motivational value of outcomes. The role of LO in outcome devaluation and reversal learning was also dissociable between anterior and posterior subregions. These novel dissociable task- and subregion-specific effects suggest a way to reconcile contradictory findings between rodent and non-human primate OFC research.

neuroscience↗