Prefrontal Cortical to Mediodorsal Thalamus Projection Neurons Regulate Posterror Adaptive Control of Behavior.

Adaptive control is the online adjustment of behavior to guide and optimize responses after errors or conflict. The neural circuits involved in monitoring and adapting behavioral performance following error are poorly understood. The prefrontal cortex (PFC) plays a critical role in this form of control. However, these brain areas are densely connected with many other regions, and it is unknown which projections are critical for adaptive behavior. Here, we tested the involvement of four distinct dorsal and ventral prefrontal cortical projections to striatal and thalamic target areas in adaptive control. We re-analyzed data from published experiments, using trial-by-trial analyses of behavior in an operant task for attention and impulsivity. We find that male rats slow their responses and perform worse following errors. Moreover, by combining retrograde labeling and chemogenetic silencing, we find that dorsomedial prefrontal pyramidal neurons that project to the lateral nucleus of the mediodorsal thalamus (MDL) are involved in posterror performance and timing of responses, specifically with unpredictable delays until stimulus presentation. Together, these data show that dorsal medial PFC (mPFC) projection neurons targeting the lateral MDT regulate adaptive control to flexibly optimize behavioral responses in goal-directed behavior.

The CADM2 Gene and Behavior: A Phenome-Wide Scan in UK-Biobank.

The cell adhesion molecule 2 (CADM2) gene has appeared among the top associations in a wide range of genome-wide association studies (GWASs). This study aims to: (1) examine how widespread the role of CADM2 is in behavioural traits, and (2) investigate trait-specific effects on CADM2 expression levels across tissues. We conducted a phenome-wide association study in UK Biobank (N = 12,211-453,349) on 242 psycho-behavioral traits, both at the SNP and the gene-level. For comparison, we repeated the analyses for other large (and high LD) genes. We found significant associations between CADM2 and 50 traits (including cognitive, risk taking, and dietary traits), many more than for the comparison genes. We show that many trait associations are reduced when taking geographical stratification into account. S-Predixcan revealed that CADM2 expression in brain tissues was significantly associated with many traits; highly significant effects were also observed for lung, mammary, and adipose tissues. In conclusion, this study shows that the role of CADM2 extends to a wide range of psycho-behavioral traits, suggesting these traits may share a common biological denominator.

Neural basis of operant behaviors maintained on the differential-reinforcement-of-low-rate (DRL) schedule in rodents.

Various schedules of reinforcement have long been used in experimental psychology to establish and maintain operant behaviors. These reinforcement contingencies have also been widely applied in preclinical psycho- and neurobiology research. However, the differential reinforcement of low-rate response (DRL) schedule has received less attention than other schedules based on response ratios or different types of intervals. Hence, little is known about the neural basis of DRL schedule-controlled behavior. Herein, we review early and recent reports of rodent experiments utilizing brain lesions and intracranial drug infusions to respectively elucidate the neural substrates and neuropharmacological basis of DRL behavior. Overall, the available evidence implies that 1) certain cortical and subcortical areas are differentially involved in the DRL behavior and 2) disruption of dopamine or serotonin neurotransmission alters DRL behavior. We further identify remaining challenges in the field and suggest future work that will be helpful for understanding the neurobehavioral mechanisms of the DRL schedule of reinforcement.

Prenatal exposure to morphine impairs attention and impulsivity in adult rats.

RATIONALE: An alarming number of neonates born with prenatal exposure to morphine has resulted from the opioid epidemic; however, the long-term effects of prenatal opioid exposure on offspring behavior remain relatively unknown. In this study, we evaluated whether prenatal exposure to the mu opioid receptor agonist, morphine, has enduring effects on cognitive functions in adult life. METHODS: On embryonic days 11-18 (E11-E18), female pregnant rats were injected subcutaneously with either morphine or saline twice daily. Adult male offspring that was prenatally exposed to saline or morphine was trained in the 5-choice serial reaction time test (5-CSRTT) to test their cognitive abilities under baseline conditions. Next, these rats were treated with saline (1 ml/kg), naloxone (1 mg/kg), and acute morphine (1, 3, 5 mg/kg), subcutaneously, once daily and following drug challenges rats were tested in the 5-CSRTT. Meanwhile, behavioral performance on training days between opioid drug challenges were analyzed to monitor possible drug-induced shifts in baseline performance. As a final experiment in order to investigate subchronic exposure to morphine, rats were injected with 5 mg/kg morphine for 5 days and then naloxone in the last day of the experiment (day 6). RESULTS: Firstly, during acquisition of a stable baseline in the training phase, rats prenatally exposed to morphine showed delayed learning of the task demands. Furthermore, under baseline responding the rats prenatally exposed to morphine showed declined inhibitory control demonstrated by increased impulsive and compulsive-like responding compared to rats prenatally exposed to saline. Moreover, acute and subchronic morphine challenges in the rats prenatally exposed to morphine caused a deficit in visuospatial attention in comparison with saline treatment as well as the rats prenatally exposed to saline. These effects were abolished by naloxone. CONCLUSION: The current findings indicate a direct causal effect of prenatal morphine exposure on inhibitory control and task learning later in life, as well as deficits in attention following morphine exposure in adulthood.

Where Dopaminergic and Cholinergic Systems Interact: A Gateway for Tuning Neurodegenerative Disorders.

Historically, many investigations into neurodegenerative diseases have focused on alterations in specific neuronal populations such as, for example, the loss of midbrain dopaminergic neurons in Parkinson's disease (PD) and loss of cholinergic transmission in Alzheimer's disease (AD). However, it has become increasingly clear that mammalian brain activities, from executive and motor functioning to memory and emotional responses, are strictly regulated by the integrity of multiple interdependent neuronal circuits. Among subcortical structures, the dopaminergic nigrostriatal and mesolimbic pathways as well as cholinergic innervation from basal forebrain and brainstem, play pivotal roles in orchestrating cognitive and non-cognitive symptoms in PD and AD. Understanding the functional interactions of these circuits and the consequent neurological changes that occur during degeneration provides new opportunities to understand the fundamental inter-workings of the human brain as well as develop new potential treatments for patients with dysfunctional neuronal circuits. Here, excerpted from a session of the European Behavioral Pharmacology Society meeting (Braga, Portugal, August 2019), we provide an update on our recent work in behavioral and cellular neuroscience that primarily focuses on interactions between cholinergic and dopaminergic systems in PD models, as well as stress in AD. These brief discussions include descriptions of (1) striatal cholinergic interneurons (CINs) and PD, (2) dopaminergic and cholinergic modulation of impulse control, and (3) the use of an implantable cell-based system for drug delivery directly the into brain and (4) the mechanisms through which day life stress, a risk factor for AD, damage protein and RNA homeostasis leading to AD neuronal malfunction.

Bi-directional regulation of cognitive control by distinct prefrontal cortical output neurons to thalamus and striatum.

The medial prefrontal cortex (mPFC) steers goal-directed actions and withholds inappropriate behavior. Dorsal and ventral mPFC (dmPFC/vmPFC) circuits have distinct roles in cognitive control, but underlying mechanisms are poorly understood. Here we use neuroanatomical tracing techniques, in vitro electrophysiology, chemogenetics and fiber photometry in rats engaged in a 5-choice serial reaction time task to characterize dmPFC and vmPFC outputs to distinct thalamic and striatal subdomains. We identify four spatially segregated projection neuron populations in the mPFC. Using fiber photometry we show that these projections distinctly encode behavior. Postsynaptic striatal and thalamic neurons differentially process synaptic inputs from dmPFC and vmPFC, highlighting mechanisms that potentially amplify distinct pathways underlying cognitive control of behavior. Chemogenetic silencing of dmPFC and vmPFC projections to lateral and medial mediodorsal thalamus subregions oppositely regulate cognitive control. In addition, dmPFC neurons projecting to striatum and thalamus divergently regulate cognitive control. Collectively, we show that mPFC output pathways targeting anatomically and functionally distinct striatal and thalamic subregions encode bi-directional command of cognitive control.

Tracing goes viral: Viruses that introduce expression of fluorescent proteins in chemically-specific neurons.

Over the last century, there has been great progress in understanding how the brain works. In particular, the last two decades have been crucial in gaining more awareness over the complex functioning of neurotransmitter systems. The use of viral vectors in neuroscience has been pivotal for such development. Exploiting the properties of viral particles, modifying them according to the research needs, and making them target chemically-specific neurons, techniques such as optogenetics and chemogenetics have been developed, which could lead to a giant step toward gene therapy for brain disorders. In this review, we aim to provide an overview of some of the most widely used viral techniques in neuroscience. We will discuss advantages and disadvantages of these methods. In particular, attention is dedicated to the pivotal role played by the introduction of adeno-associated virus and the retrograde tracer canine-associated-2 Cre virus in order to achieve optimal visualization, and interrogation, of chemically-specific neuronal populations and their projections.

Prefrontal Cortical Projection Neurons Targeting Dorsomedial Striatum Control Behavioral Inhibition.

A neural pathway from prefrontal cortex (PFC) to dorsal striatum (DS) has been suggested to mediate cognitive control of behavior, including proactive inhibitory control and attention. However, a direct causal demonstration thereof is lacking. Here, we show that selective chemogenetic silencing of corticostriatal PFC neurons in rats increases premature responses. Wireless single-unit electrophysiological recordings of optogenetically identified corticostriatal PFC neurons revealed that the majority of these neurons encode behavioral trial outcome with persistent changes in firing rate. Attentional parameters were not affected by silencing corticostriatal PFC neurons, suggesting that these projection neurons encode a specific subset of cognitive behaviors. Compared to the general non-identified neuronal population in the PFC, frontostriatal neurons showed selective engagement during periods of inhibitory control. Our results demonstrate a role for corticostriatal neurons in inhibitory control and possibly suggest that distinct domains of cognitive control over behavior are encoded by specific projection neuron populations.

Personality driven alcohol and drug abuse: New mechanisms revealed.

While the majority of the regular consumers of alcohol controls their consumption well over life span and even takes instrumentalization benefits from it, a minority, but yet high total number of users develops an alcohol addiction. It has long been known that particular personality types are more addiction prone than others. Here we review recent progress in the understanding of neurobiological pathways that determine personality and facilitate drug abuse. Novel approaches to characterize personality traits leading to addiction proneness in social settings in mice are discussed. A common genetic and neurobiological base for the behavioural traits of sensation seeking or a depressed phenotype and escalating alcohol consumption are reviewed. Furthermore, recent progress on how social and cognitive factors, including impulsivity and decision making, act at brain level to make an individual more vulnerable to alcohol abuse, are discussed. Altogether, this review provides an update on brain mechanisms underlying a broad spectrum of personality traits that make an individual more prone to alcohol and drug abuse and addiction.

The Neuropharmacology of Impulsive Behaviour, an Update.

Neuropharmacological interventions in preclinical translational models of impulsivity have tremendously contributed to a better understanding of the neurochemistry and neural basis of impulsive behaviour. In this regard, much progress has been made over the last years, also due to the introduction of novel techniques in behavioural neuroscience such as optogenetics and chemogenetics. In this chapter, we will provide an update of how the behavioural pharmacology field has progressed and built upon existing data since an earlier review we wrote in 2008. To this aim, we will first give a brief background on preclinical translational models of impulsivity. Next, recent interesting evidence of monoaminergic modulation of impulsivity will be highlighted with a focus on the neurotransmitters dopamine and noradrenaline. Finally, we will close the chapter by discussing some novel directions and drug leads in the neuropharmacological modulation of impulsivity.

The role of impulsivity as predisposing behavioural trait in different aspects of alcohol self-administration in rats.

BACKGROUND: Therapeutic interventions to promote abstinence and prevent relapse in alcohol use disorder (AUD) are limitedly available. Therefore, targeting risk factors in the onset and maintenance of AUD could pose an interesting alternative treatment strategy. In this regard, over the last decade trait impulsivity has received considerable attention as such a risk factor predisposing substance dependence both in clinical populations and preclinical rodent studies. This study investigated whether different forms of impulsivity (action versus choice) predict distinct stages of instrumental alcohol self-administration, extinction and cue-induced relapse. METHODS: Two cohorts of n = 48 rats each were trained in an operant tasks for either impulsive action or impulsive choice. Subsequently, high and low impulsive rats were then tested in an alcohol self-administration and relapse model and following this retested in the impulsivity tasks to evaluate possible changes in impulsivity levels. RESULTS: The current data show that neither impulsive action, nor impulsive choice predict the extent to which rats consume alcohol and the extent to which rats are motivated to self-administer alcohol. Moreover, extinction of responding for alcohol and cue-induced relapse was not predicted by impulsivity. Interestingly, rats and most prominently low impulsive rats became more impulsive after the alcohol self-administration procedure. Although due to employed experimental design it is not clear whether this resulted from alcohol consumption or alcohol abstinence. CONCLUSION: Together, these findings lend further support for the notion of a unidirectional relationship between self-administration of the depressant drug alcohol and impulsivity.

Author Correction: Prefrontal cortical ChAT-VIP interneurons provide local excitation by cholinergic synaptic transmission and control attention.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Prefrontal cortical ChAT-VIP interneurons provide local excitation by cholinergic synaptic transmission and control attention.

Neocortical choline acetyltransferase (ChAT)-expressing interneurons are a subclass of vasoactive intestinal peptide (ChAT-VIP) neurons of which circuit and behavioural function are unknown. Here, we show that ChAT-VIP neurons directly excite neighbouring neurons in several layers through fast synaptic transmission of acetylcholine (ACh) in rodent medial prefrontal cortex (mPFC). Both interneurons in layers (L)1-3 as well as pyramidal neurons in L2/3 and L6 receive direct inputs from ChAT-VIP neurons mediated by fast cholinergic transmission. A fraction (10-20%) of postsynaptic neurons that received cholinergic input from ChAT-VIP interneurons also received GABAergic input from these neurons. In contrast to regular VIP interneurons, ChAT-VIP neurons did not disinhibit pyramidal neurons. Finally, we show that activity of these neurons is relevant for behaviour and they control attention behaviour distinctly from basal forebrain ACh inputs. Thus, ChAT-VIP neurons are a local source of cortical ACh that directly excite neurons throughout cortical layers and contribute to attention.

An automated home-cage-based 5-choice serial reaction time task for rapid assessment of attention and impulsivity in rats.

RATIONALE: The 5-choice serial reaction time task (5-CSRTT) is a widely used operant task for measuring attention and motor impulsivity in rodents. Training animals in this task requires an extensive period of daily operant sessions. Recently, a self-paced, automated version of this task has been developed for mice, which substantially reduces training time. Whether a similar approach is effective for rats is currently unknown. OBJECTIVE: Here, we tested whether attention and impulsivity can be assessed in rats with a self-paced version of the 5-CSRTT. METHODS: Operant boxes were connected to home-cages with tunnels. Two groups of rats self-paced their training by means of an automated script. The first group of animals was allowed unlimited access (UA) to start trials in the task; for the second group, trial availability was restricted to the first 2.5 h of the dark cycle (TR). Task parameter manipulations, such as variable inter-trial intervals and stimulus durations as well as pharmacological challenges with scopolamine, were tested to validate the task. RESULTS: Self-paced training took less than 1 week. Animals in the UA group showed higher levels of omissions compared with the TR group. In both protocols, variable inter-trial intervals increased impulsivity, and variable stimulus durations decreased attentional performance. Scopolamine affected cognitive performance in the TR group only. CONCLUSIONS: Home-cage-based training of the 5-CSRTT in rats, especially the TR protocol, presents a valid and fast alternative for measuring attention and impulsivity.

Striatal alcohol cue-reactivity is stronger in male than female problem drinkers.

Despite apparent sex differences in the development and treatment of alcohol use disorder, relatively little is known about the underlying neural mechanisms. In this study, we therefore investigated neural cue-reactivity in a sample of male (n = 28) and female (n = 27) problem drinkers (matched on age and alcohol use severity) with an average alcohol use disorder identification test score of 12 which is indicative of a likely alcohol use disorder. Neural cue-reactivity data were extracted from four regions of interest: the ventral and dorsal striatum and the ventral and dorsal anterior cingulate cortex, with a significance level set at p < 0.05. While the cue-reactivity paradigm induced similar levels of self-reported craving in men and women, visual alcohol cues induced significantly stronger striatal activation in men compared to drinkers. While sex differences in ventral striatal cue-reactivity were partly explained by sex differences in alcohol intake, cannabis use, negative affect and anxiety, this was not the case for sex differences in dorsal striatal cue-reactivity. These results suggest that alcohol cues are differentially processed by men and women and that the neurobiological mechanisms behind cue-reactivity differ between the sexes. Consequently, paradigms using alcohol-related pictures may not be optimal to induce cue-reactivity in female drinkers and may not be optimal to measure neurobiological markers of alcohol use severity and relapse. Future alcohol cue-reactivity studies should, in addition to including both men and women, include different types of cues (e.g., stressors and imagery in addition to pictures) to assess sex differences in alcohol cue-reactivity.

Optogenetic and chemogenetic approaches to manipulate attention, impulsivity and behavioural flexibility in rodents.

Studies manipulating neural activity acutely with optogenetic or chemogenetic intervention in behaving rodents have increased considerably in recent years. More often, these circuit-level neural manipulations are tested within an existing framework of behavioural testing that strives to model complex executive functions or symptomologies relevant to multidimensional psychiatric disorders in humans, such as attentional control deficits, impulsivity or behavioural (in)flexibility. This methods perspective argues in favour of carefully implementing these acute circuit-based approaches to better understand and model cognitive symptomologies or their similar isomorphic animal behaviours, which often arise and persist in overlapping brain circuitries. First, we offer some practical considerations for combining long-term, behavioural paradigms with optogenetic or chemogenetic interventions. Next, we examine how cell-type or projection-specific manipulations to the ascending neuromodulatory systems, local brain region or descending cortical glutamatergic projections influence aspects of cognitive control. For this, we primarily focus on the influence exerted on attentional and motor impulsivity performance in the (3-choice or) 5-choice serial reaction time task, and impulsive, risky or inflexible choice biases during alternative preference, reward discounting or reversal learning tasks.

Examination of the effects of cannabinoid ligands on decision making in a rat gambling task.

Although exposure to delta-9-tetrahydrocannabinol (THC) is perceived to be relatively harmless, mounting evidence has begun to show that it is associated with a variety of cognitive deficits, including poor decision making. THC-induced impairments in decision making are thought to be the result of cannabinoid CB1 receptor activation, and although clinical literature suggests that chronic activation via THC contributes to perturbations in decision making, acute CB1 receptor modulation has yielded mixed results. Using an animal model to examine how CB1-specific ligands impact choice biases would provide significant insight as to how recruitment of the endocannabinoid system may influence decision making. Here, we used the rat gambling task (rGT), a validated analogue of the human Iowa Gambling Task, to assess baseline decision making preferences in male Wistar rats. After acquisition rGT performance was measured. Animals were challenged with the CB1 receptor antagonist rimonabant, the partial agonist THC, and the synthetic agonist WIN55,212-2. Animals were also treated acutely with the fatty acid amide hydrolase (FAAH) inhibitor URB597 to selectively upregulate the endocannabinoid anandamide. Blockade of the CB1 receptor produced a trend improvement in decision making in animals who preferred the advantageous task options, yet left choice unaffected in risk-prone rats. Neither CB1 receptor agonist had strong effects on decision making, but a high dose THC decreased premature responses, whereas WIN55,212-2 did the opposite. URB597 did not affect task performance. These results indicate that although chronic CB1 receptor activation may be associated with impaired decision making, acute modulation has modest effects on choice and instead may play a substantive role in regulating impulsive responding.

A high working memory load prior to memory retrieval reduces craving in non-treatment seeking problem drinkers.

BACKGROUND: Reconsolidation-based interventions have been suggested to be a promising treatment strategy for substance use disorders. In this study, we aimed to investigate the effectiveness of a working memory intervention to interfere with the reconsolidation of alcohol-related memories in a sample of non-treatment seeking heavy drinkers. METHODS: Participants were randomized to one of the two conditions that underwent a 3-day intervention: in the experimental condition, a 30-min working memory training was performed immediately after a 15-min memory retrieval session (i.e., within the memory reconsolidation time-window), whereas in the control condition, the working memory training was performed prior to a memory retrieval session. RESULTS: In contrast to our original hypothesis, a high working memory load after memory retrieval did not interfere with the reconsolidation of those memories while a high working memory load prior to memory retrieval (the original control condition) strongly reduced retrieval-induced craving and craving for alcohol at follow-up. CONCLUSION: Whereas the neurocognitive mechanism behind this effect needs to be further investigated, the current findings suggest that, if replicated, working memory training prior to addiction-related memory retrieval has the potential to become an effective (adjunctive) intervention in the treatment of substance use disorders.

Dissociable effects of cocaine and yohimbine on impulsive action and relapse to cocaine seeking.

RATIONALE: A strong association has been demonstrated between various forms of impulsivity and addiction-like behavior in both humans and rats. OBJECTIVES: In this study, we investigated how impulsive action, as measured in the 5-choice serial reaction time task (5-CSRTT), is affected during various stages of cocaine taking and seeking and by relapse-provoking stimuli in animals that were trained both in an intravenous cocaine self-administration paradigm and in the 5-CSRTT. METHODS: Rats were concurrently trained in the 5-CSRTT and cocaine self-administration protocol, and subsequently, the effects of cocaine (7.5 mg/kg) and the pharmacological stressor yohimbine (1.25 mg/kg) were tested in both paradigms. RESULTS: Cocaine self-administration (5 h/day) transiently altered impulsive action and increased errors of omission in the 5-CSRTT. Pharmacological challenges with cocaine and yohimbine induced increments in impulsive action and reinstated cocaine-seeking responses within the same animals. Further analyses revealed that the effects of cocaine and yohimbine on impulsive action did not correlate with their effects on reinstatement of cocaine seeking. CONCLUSIONS: These data suggest that although impulsive action and relapse can be pharmacologically modulated in the same direction within individuals, these effects appear not to be directly coupled.

Deep Brain Stimulation of the Nucleus Accumbens Core Affects Trait Impulsivity in a Baseline-Dependent Manner.

Deep brain stimulation (DBS) of the nucleus accumbens (NA) is explored as a treatment for refractory psychiatric disorders, such as obsessive-compulsive disorder (OCD), depressive disorder (MDD), and substance use disorder (SUD). A common feature of some of these disorders is pathological impulsivity. Here, the effects of NAcore DBS on impulsive choice and impulsive action, two distinct forms of impulsive behavior, were investigated in translational animal tasks, the delayed reward task (DRT) and five-choice serial reaction time task (5-CSRTT), respectively. In both tasks, the effects of NAcore DBS were negatively correlated with baseline impulsive behavior, with more pronounced effects in the 5-CSRTT. To further examine the effects of DBS on trait impulsive action, rats were screened for high (HI) and low (LI) impulsive responding in the 5-CSRTT. NAcore DBS decreased impulsive, premature responding in HI rats under conventional conditions. However, upon challenged conditions to increase impulsive responding, NAcore DBS did not alter impulsivity. These results strongly suggest a baseline-dependent effect of DBS on impulsivity, which is in line with clinical observations.