A consistent map in the medial entorhinal cortex supports spatial memory.

The medial entorhinal cortex (MEC) is hypothesized to function as a cognitive map for memory-guided navigation. How this map develops during learning and influences memory remains unclear. By imaging MEC calcium dynamics while mice successfully learned a novel virtual environment over ten days, we discovered that the dynamics gradually became more spatially consistent and then stabilized. Additionally, grid cells in the MEC not only exhibited improved spatial tuning consistency, but also maintained stable phase relationships, suggesting a network mechanism involving synaptic plasticity and rigid recurrent connectivity to shape grid cell activity during learning. Increased c-Fos expression in the MEC in novel environments further supports the induction of synaptic plasticity. Unsuccessful learning lacked these activity features, indicating that a consistent map is specific for effective spatial memory. Finally, optogenetically disrupting spatial consistency of the map impaired memory-guided navigation in a well-learned environment. Thus, we demonstrate that the establishment of a spatially consistent MEC map across learning both correlates with, and is necessary for, successful spatial memory.

A consistent map in the medial entorhinal cortex supports spatial memory.

The medial entorhinal cortex (MEC) is hypothesized to function as a cognitive map for memory-guided navigation. How this map develops during learning and influences memory remains unclear. By imaging MEC calcium dynamics while mice successfully learned a novel virtual environment over ten days, we discovered that the dynamics gradually became more spatially consistent and then stabilized. Additionally, grid cells in the MEC not only exhibited improved spatial tuning consistency, but also maintained stable phase relationships, suggesting a network mechanism involving synaptic plasticity and rigid recurrent connectivity to shape grid cell activity during learning. Increased c-Fos expression in the MEC in novel environments further supports the induction of synaptic plasticity. Unsuccessful learning lacked these activity features, indicating that a consistent map is specific for effective spatial memory. Finally, optogenetically disrupting spatial consistency of the map impaired memory-guided navigation in a well-learned environment. Thus, we demonstrate that the establishment of a spatially consistent MEC map across learning both correlates with, and is necessary for, successful spatial memory.

Somatostatin peptide signaling dampens cortical circuits and promotes exploratory behavior.

We sought to characterize the unique role of somatostatin (SST) in the prelimbic (PL) cortex in mice. We performed slice electrophysiology in pyramidal and GABAergic neurons to characterize the pharmacological mechanism of SST signaling and fiber photometry of GCaMP6f fluorescent calcium signals from SST neurons to characterize the activity profile of SST neurons during exploration of an elevated plus maze (EPM) and open field test (OFT). We used local delivery of a broad SST receptor (SSTR) agonist and antagonist to test causal effects of SST signaling. SSTR activation hyperpolarizes layer 2/3 pyramidal neurons, an effect that is recapitulated with optogenetic stimulation of SST neurons. SST neurons in PL are activated during EPM and OFT exploration, and SSTR agonist administration directly into the PL enhances open arm exploration in the EPM. This work describes a broad ability for SST peptide signaling to modulate microcircuits within the prefrontal cortex and related exploratory behaviors.

Prefrontal Interneurons: Populations, Pathways, and Plasticity Supporting Typical and Disordered Cognition in Rodent Models.

Prefrontal cortex (PFC) inhibitory microcircuits regulate the gain and timing of pyramidal neuron firing, coordinate neural ensemble interactions, and gate local and long-range neural communication to support adaptive cognition and contextually tuned behavior. Accordingly, perturbations of PFC inhibitory microcircuits are thought to underlie dysregulated cognition and behavior in numerous psychiatric diseases and relevant animal models. This review, based on a Mini-Symposium presented at the 2022 Society for Neuroscience Meeting, highlights recent studies providing novel insights into: (1) discrete medial PFC (mPFC) interneuron populations in the mouse brain; (2) mPFC interneuron connections with, and regulation of, long-range mPFC afferents; and (3) circuit-specific plasticity of mPFC interneurons. The contributions of such populations, pathways, and plasticity to rodent cognition are discussed in the context of stress, reward, motivational conflict, and genetic mutations relevant to psychiatric disease.

Hippocampal-Prefrontal Theta Transmission Regulates Avoidance Behavior.

Long-range synchronization of neural oscillations correlates with distinct behaviors, yet its causal role remains unproven. In mice, tests of avoidance behavior evoke increases in theta-frequency (∼8 Hz) oscillatory synchrony between the ventral hippocampus (vHPC) and medial prefrontal cortex (mPFC). To test the causal role of this synchrony, we dynamically modulated vHPC-mPFC terminal activity using optogenetic stimulation. Oscillatory stimulation at 8 Hz maximally increased avoidance behavior compared to 2, 4, and 20 Hz. Moreover, avoidance behavior was selectively increased when 8-Hz stimulation was delivered in an oscillatory, but not pulsatile, manner. Furthermore, 8-Hz oscillatory stimulation enhanced vHPC-mPFC neurotransmission and entrained neural activity in the vHPC-mPFC network, resulting in increased synchrony between vHPC theta activity and mPFC spiking. These data suggest a privileged role for vHPC-mPFC theta-frequency communication in generating avoidance behavior and provide direct evidence that synchronized oscillations play a role in facilitating neural transmission and behavior.

Active Zone Proteins RIM1αß Are Required for Normal Corticostriatal Transmission and Action Control.

Dynamic regulation of synaptic transmission at cortical inputs to the dorsal striatum is considered critical for flexible and efficient action learning and control. Presynaptic mechanisms governing the properties and plasticity of glutamate release from these inputs are not fully understood, and the corticostriatal synaptic processes that support normal action learning and control remain unclear. Here we show in male and female mice that conditional deletion of presynaptic proteins RIM1αß (RIM1) from excitatory cortical neurons impairs corticostriatal synaptic transmission in the dorsolateral striatum. Key forms of presynaptic G-protein-coupled receptor-mediated short- and long-term striatal plasticity are spared following RIM1 deletion. Conditional RIM1 KO mice show heightened novelty-induced locomotion and impaired motor learning on the accelerating rotarod. They further show heightened self-paced instrumental responding for food and impaired learning of a habitual instrumental response strategy. Together, these findings reveal a selective role for presynaptic RIM1 in neurotransmitter release at prominent basal ganglia synapses, and provide evidence that RIM1-dependent processes help to promote the refinement of skilled actions, constrain goal-directed behaviors, and support the learning and use of habits.SIGNIFICANCE STATEMENT Our daily functioning hinges on the ability to flexibly and efficiently learn and control our actions. How the brain encodes these capacities is unclear. Here we identified a selective role for presynaptic proteins RIM1αß in controlling glutamate release from cortical inputs to the dorsolateral striatum, a brain structure critical for action learning and control. Behavioral analysis of mice with restricted genetic deletion of RIM1αß further revealed roles for RIM1αß-dependent processes in the learning and refinement of motor skills and the balanced expression of goal-directed and habitual actions.

The cannabinoid-1 receptor is abundantly expressed in striatal striosomes and striosome-dendron bouquets of the substantia nigra.

Presynaptic cannabinoid-1 receptors (CB1-R) bind endogenous and exogenous cannabinoids to modulate neurotransmitter release. CB1-Rs are expressed throughout the basal ganglia, including striatum and substantia nigra, where they play a role in learning and control of motivated actions. However, the pattern of CB1-R expression across different striatal compartments, microcircuits and efferent targets, and the contribution of different CB1-R-expressing neurons to this pattern, are unclear. We use a combination of conventional techniques and novel genetic models to evaluate CB1-R expression in striosome (patch) and matrix compartments of the striatum, and in nigral targets of striatal medium spiny projection neurons (MSNs). CB1-R protein and mRNA follow a descending dorsolateral-to-ventromedial intensity gradient in the caudal striatum, with elevated expression in striosomes relative to the surrounding matrix. The lateral predominance of striosome CB1-Rs contrasts with that of the classical striosomal marker, the mu opioid receptor (MOR), which is expressed most prominently in rostromedial striosomes. The dorsolateral-to-ventromedial CB1-R gradient is similar to Drd2 dopamine receptor immunoreactivity and opposite to Substance P. This topology of CB1-R expression is maintained downstream in the globus pallidus and substantia nigra. Dense CB1-R-expressing striatonigral fibers extend dorsally within the substantia nigra pars reticulata, and colocalize with bundles of ventrally extending, striosome-targeted, dendrites of dopamine-containing neurons in the substantia nigra pars compacta (striosome-dendron bouquets). Within striatum, CB1-Rs colocalize with fluorescently labeled MSN collaterals within the striosomes. Cre recombinase-mediated deletion of CB1-Rs from cortical projection neurons or MSNs, and MSN-selective reintroduction of CB1-Rs in knockout mice, demonstrate that the principal source of CB1-Rs in dorsolateral striosomes is local MSN collaterals. These data suggest a role for CB1-Rs in caudal dorsolateral striosome collaterals and striosome-dendron bouquet projections to lateral substantia nigra, where they are anatomically poised to mediate presynaptic disinhibition of both striosomal MSNs and midbrain dopamine neurons in response to endocannabinoids and cannabinomimetics.

The dynamics of disordered dialogue: Prefrontal, hippocampal and thalamic miscommunication underlying working memory deficits in schizophrenia.

The prefrontal cortex is central to the orchestrated brain network communication that gives rise to working memory and other cognitive functions. Accordingly, working memory deficits in schizophrenia are increasingly thought to derive from prefrontal cortex dysfunction coupled with broader network disconnectivity. How the prefrontal cortex dynamically communicates with its distal network partners to support working memory and how this communication is disrupted in individuals with schizophrenia remain unclear. Here we review recent evidence that prefrontal cortex communication with the hippocampus and thalamus is essential for normal spatial working memory, and that miscommunication between these structures underlies spatial working memory deficits in schizophrenia. We focus on studies using normal rodents and rodent models designed to probe schizophrenia-related pathology to assess the dynamics of neural interaction between these brain regions. We also highlight recent preclinical work parsing roles for long-range prefrontal cortex connections with the hippocampus and thalamus in normal and disordered spatial working memory. Finally, we discuss how emerging rodent endophenotypes of hippocampal- and thalamo-prefrontal cortex dynamics in spatial working memory could translate into richer understanding of the neural bases of cognitive function and dysfunction in humans.

Parallel, but Dissociable, Processing in Discrete Corticostriatal Inputs Encodes Skill Learning.

Changes in cortical and striatal function underlie the transition from novel actions to refined motor skills. How discrete, anatomically defined corticostriatal projections function in vivo to encode skill learning remains unclear. Using novel fiber photometry approaches to assess real-time activity of associative inputs from medial prefrontal cortex to dorsomedial striatum and sensorimotor inputs from motor cortex to dorsolateral striatum, we show that associative and sensorimotor inputs co-engage early in action learning and disengage in a dissociable manner as actions are refined. Disengagement of associative, but not sensorimotor, inputs predicts individual differences in subsequent skill learning. Divergent somatic and presynaptic engagement in both projections during early action learning suggests potential learning-related in vivo modulation of presynaptic corticostriatal function. These findings reveal parallel processing within associative and sensorimotor circuits that challenges and refines existing views of corticostriatal function and expose neuronal projection- and compartment-specific activity dynamics that encode and predict action learning.

Inhibition of presynaptic calcium transients in cortical inputs to the dorsolateral striatum by metabotropic GABA(B) and mGlu2/3 receptors.

Cortical inputs to the dorsolateral striatum (DLS) are dynamically regulated during skill learning and habit formation, and are dysregulated in disorders characterized by impaired action control. Therefore, a mechanistic investigation of the processes regulating corticostriatal transmission is key to understanding DLS-associated circuit function, behaviour and pathology. Presynaptic GABA(B) and group II metabotropic glutamate (mGlu2/3) receptors exert marked inhibitory control over corticostriatal glutamate release in the DLS, yet the signalling pathways through which they do so are unclear. We developed a novel approach using the genetically encoded calcium (Ca(2+) ) indicator GCaMP6 to assess presynaptic Ca(2+) in corticostriatal projections to the DLS. Using simultaneous photometric presynaptic Ca(2+) and striatal field potential recordings, we report that relative to P/Q-type Ca(2+) channels, N-type channels preferentially contributed to evoked presynaptic Ca(2+) influx in motor cortex projections to, and excitatory transmission in, the DLS. Activation of GABA(B) or mGlu2/3 receptors inhibited both evoked presynaptic Ca(2+) transients and striatal field potentials. mGlu2/3 receptor-mediated depression did not require functional N-type Ca(2+) channels, but was attenuated by blockade of P/Q-type channels. These findings reveal presynaptic mechanisms of inhibitory modulation of corticostriatal function that probably contribute to the selection and shaping of behavioural repertoires.

Brain BLAQ: Post-hoc thick-section histochemistry for localizing optogenetic constructs in neurons and their distal terminals.

Optogenetic constructs have revolutionized modern neuroscience, but the ability to accurately and efficiently assess their expression in the brain and associate it with prior functional measures remains a challenge. High-resolution imaging of thick, fixed brain sections would make such post-hoc assessment and association possible; however, thick sections often display autofluorescence that limits their compatibility with fluorescence microscopy. We describe and evaluate a method we call "Brain BLAQ" (Block Lipids and Aldehyde Quench) to rapidly reduce autofluorescence in thick brain sections, enabling efficient axon-level imaging of neurons and their processes in conventional tissue preparations using standard epifluorescence microscopy. Following viral-mediated transduction of optogenetic constructs and fluorescent proteins in mouse cortical pyramidal and dopaminergic neurons, we used BLAQ to assess innervation patterns in the striatum, a region in which autofluorescence often obscures the imaging of fine neural processes. After BLAQ treatment of 250-350 µm-thick brain sections, axons and puncta of labeled afferents were visible throughout the striatum using a standard epifluorescence stereomicroscope. BLAQ histochemistry confirmed that motor cortex (M1) projections preferentially innervated the matrix component of lateral striatum, whereas medial prefrontal cortex projections terminated largely in dorsal striosomes and distinct nucleus accumbens subregions. Ventral tegmental area dopaminergic projections terminated in a similarly heterogeneous pattern within nucleus accumbens and ventral striatum. Using a minimal number of easily manipulated and visualized sections, and microscopes available in most neuroscience laboratories, BLAQ enables simple, high-resolution assessment of virally transduced optogenetic construct expression, and post-hoc association of this expression with molecular markers, physiology and behavior.

Optogenetic measurement of presynaptic calcium transients using conditional genetically encoded calcium indicator expression in dopaminergic neurons.

Calcium triggers dopamine release from presynaptic terminals of midbrain dopaminergic (mDA) neurons in the striatum. However, calcium transients within mDA axons and axon terminals are difficult to study and little is known about how they are regulated. Here we use a newly-developed method to measure presynaptic calcium transients (PreCaTs) in axons and terminals of mDA neurons with a genetically encoded calcium indicator (GECI) GCaMP3 expressed in transgenic mice. Using a photomultiplier tube-based system, we measured electrical stimulation-induced PreCaTs of mDA neurons in dorsolateral striatum slices from these mice. Single-pulse stimulation produced a transient increase in fluorescence that was completely blocked by a combination of N- and P/Q-type calcium channel blockers. DA and cholinergic, but not serotoninergic, signaling pathways modulated the PreCaTs in mDA fibers. These findings reveal heretofore unexplored dynamic modulation of presynaptic calcium in nigrostriatal terminals.

Repeated intravenous administrations of teneurin-C terminal associated peptide (TCAP)-1 attenuates reinstatement of cocaine seeking by corticotropin-releasing factor (CRF) in rats.

The teneurin c-terminal associated peptides (TCAP) have been implicated in the regulation of the stress response, possibly via a corticotropin-releasing factor (CRF)-related mechanism. We have previously shown that repeated intracerebroventricular (ICV) injections of TCAP-1 attenuate the reinstatement of cocaine seeking by CRF in rats. Here, we determined whether intravenous (IV) administrations of TCAP-1 would likewise attenuate CRF-induced reinstatement, and whether this effect would vary depending on the rat's history of cocaine self administration. Rats were trained to self-administer cocaine for 10 days, during once daily sessions that were either 3h ("short access"; ShA) or 6h ("long access"; LgA). Rats were then given five daily injections of TCAP-1 (0, 300, or 3,000 pmol, IV) in their home cage. Subsequently, they were returned to the self-administration chambers where extinction of cocaine seeking and testing for CRF-induced reinstatement of cocaine seeking was carried out. Repeated IV administrations of TCAP-1 were efficacious in attenuating CRF-induced reinstatement of cocaine seeking, but at different doses in ShA and LgA rats. Taken together, the findings extend previous work showing a consistent effect of repeated ICV TCAP-1 on CRF-induced reinstatement of cocaine seeking, and point to a potential therapeutic benefit of TCAP-1 in attenuating cocaine seeking behaviors.

Opioids induce dissociable forms of long-term depression of excitatory inputs to the dorsal striatum.

As prescription opioid analgesic abuse rates rise, so does the need to understand the long-term effects of opioid exposure on brain function. The dorsal striatum is an important site for drug-induced neuronal plasticity. We found that exogenously applied and endogenously released opioids induced long-term depression (OP-LTD) of excitatory inputs to the dorsal striatum in mice and rats. Mu and delta OP-LTD, although both being presynaptically expressed, were dissociable in that they summated, differentially occluded endocannabinoid-LTD and inhibited different striatal inputs. Kappa OP-LTD showed a unique subregional expression in striatum. A single in vivo exposure to the opioid analgesic oxycodone disrupted mu OP-LTD and endocannabinoid-LTD, but not delta or kappa OP-LTD. These data reveal previously unknown opioid-mediated forms of long-term striatal plasticity that are differentially affected by opioid analgesic exposure and are likely important mediators of striatum-dependent learning and behavior.

Toward a functional neuroanatomical signature of bipolar disorder: quantitative evidence from the neuroimaging literature.

The present meta-analysis quantitatively reviewed the functional neuroimaging literature on bipolar disorder (BPD) to better characterize its neuroanatomical signature with respect to the influence of mood state, test conditions, and clinical demographics on regional brain activation. Fifty-five functional neuroimaging studies published between 1987 and 2010 met criteria for inclusion, encompassing a total of 774 adult patients with BPD and 810 healthy adult controls. A meta-analysis was conducted comparing the activation states of multiple brain regions in BPD patients and control subjects. Despite heterogeneity across studies, our findings support the view that limbic hyperactivity and frontal hypoactivity are neurobiological correlates of BPD. Our findings also highlight the involvement of many brain regions and circuits, as well as the critical role of mood state and test conditions in the functional impairments of BPD. This review represents the first attempt to quantitatively articulate the magnitude of functional brain abnormality in BPD, and, in so doing, provides a synthesis of evidence in line with current network models of the disorder. Overall, this review offers support for, and seeks to help guide, the continued use of functional neuroimaging as an informative probe into the complex neurobiology of BPD.

A procedure for studying the footshock-induced reinstatement of cocaine seeking in laboratory rats.

The most insidious aspect of drug addiction is the high propensity for relapse. Animal models of relapse, known as reinstatement procedures, have been used extensively to study the neurobiology and phenomenology of relapse to drug use. Although procedural variations have emerged over the past several decades, the most conventional reinstatement procedures are based on the drug self-administration (SA) model. In this model, an animal is trained to perform an operant response to obtain drug. Subsequently, the behavior is extinguished by withholding response-contingent reinforcement. Reinstatement of drug seeking is then triggered by a discrete event, such as an injection of the training drug, re-exposure to drug-associated cues, or exposure to a stressor. Reinstatement procedures were originally developed to study the ability of acute non-contingent exposure to the training drug to reinstate drug seeking in rats and monkeys. Reinstatement procedures have since been modified to study the role of environmental stimuli, including drug-associated cues and exposure to various forms of stress, in relapse to drug seeking. Over the past 15 years, a major focus of the reinstatement literature has been on the role of stress in drug relapse. One of the most commonly used forms of stress for studying this relationship is acute exposures to mild, intermittent, electric footshocks. The ability of footshock stress to induce reinstatement of drug seeking was originally demonstrated by Shaham and colleagues (1995) in rats with a history of intravenous heroin SA(5). Subsequently, the effect was generalized to rats with histories of intravenous cocaine, methamphetamine, and nicotine SA, as well as oral ethanol SA. Although footshock-induced reinstatement of drug seeking can be achieved reliably and robustly, it is an effect that tends to be sensitive to certain parametrical variables. These include the arrangement of extinction and reinstatement test sessions, the intensity and duration of footshock stress, and the presence of drug-associated cues during extinction and testing for reinstatement. Here we present a protocol for footshock-induced reinstatement of cocaine seeking that we have used with consistent success to study the relationship between stress and cocaine seeking.

Teneurin C-terminal associated peptide-1 blocks the effects of corticotropin-releasing factor on reinstatement of cocaine seeking and on cocaine-induced behavioural sensitization.

BACKGROUND AND PURPOSE: The stress-related neuropeptide, corticotropin-releasing factor (CRF), has become an important focus of studies of cocaine addiction, and in particular, the effects of stress on cocaine-related behaviours. A recently discovered peptide system, the teneurin C-terminal associated peptides (TCAP), has been implicated in the regulation of the stress response, via a CRF-related mechanism. Here we have determined whether treatment with TCAP-1, a synthetic analogue of TCAP, modulated two cocaine-related behaviours induced by CRF: reinstatement of cocaine seeking, and expression of cocaine-induced behavioural sensitization. EXPERIMENTAL APPROACH: In Experiment 1, rats trained to self-administer cocaine were given acute or repeated (once daily for 5 days) i.c.v. injections of TCAP-1 before tests for reinstatement in response to CRF (105 pmol, i.c.v.), intermittent footshock stress (0.9 mA), or cocaine (15 mg·kg⁻¹, i.p.). In Experiment 2, rats pre-exposed to cocaine (15-30 mg·kg⁻¹, i.p.) or saline for 7 days were treated with TCAP-1 (once daily for 5 days; i.c.v.) and subsequently tested for locomotor responses to CRF (105 pmol, i.c.v.) or cocaine (15 mg·kg⁻¹, i.p.). KEY RESULTS: Five day pre-exposure with TCAP-1 blocked CRF-, but not footshock- or cocaine-induced reinstatement of cocaine seeking; acute pretreatment with TCAP-1 was without effect in all test conditions. Similarly, repeated TCAP-1 pre-exposure blocked the cocaine-sensitized locomotor response to CRF, but not to cocaine. CONCLUSIONS AND IMPLICATIONS: Repeated TCAP-1 exposure induced robust and selective inhibition of cocaine-related behavioural responses to CRF, suggesting that TCAP-1 may normalize signalling within CRF systems dysregulated by cocaine exposure.

Age-related effects of acute nicotine on behavioural and neuronal measures of anxiety.

Adolescence is considered a period of enhanced vulnerability to the initiation of tobacco use. Biological differences in the sensitivity of adolescents and adults to the anxiogenic and anxiolytic effects of nicotine may contribute to this heightened vulnerability. Here, we investigated the age-dependency of the effects of acute nicotine on anxiety-related behaviour and neurotransmission. In Experiment 1, male adolescent (P33-37) and adult (P65-69) Long-Evans rats received nicotine (0, 0.4 or 0.8 mg/kg,s.c.) prior to testing using two measures of anxiety, the elevated plus maze (EPM) and light-dark (LD) transition box. In Experiment 2, in situ hybridization was used to assess, in different male adolescent and adult rats, CRF mRNA expression in the BNST, PVN and CeA in response to acute nicotine. In the EPM, adult rats displayed less anxious behaviour than adolescents. Nicotine (0.4, 0.8 mg/kg) increased open and closed arm entries in adolescent rats, suggesting increased general activity, but it did not affect behaviour in the LD box. CRF mRNA expression was elevated in PVN of adolescent rats, relative to adults. Nicotine, however, had no effect on CRF mRNA expression in the BNST, PVN or CeA. The present findings suggest that adolescents are more sensitive to the general activational, rather than anxiety-related, effects of nicotine, and that CRF mRNA expression in stress-related brain regions does not correlate with these effects. This work further characterizes the age-related differences in the anxiety-related effects of nicotine, and provides insight into potential factors influencing vulnerability to tobacco abuse.

Effects of repeated yohimbine on the extinction and reinstatement of cocaine seeking.

Acute exposure to the pharmacological stressor yohimbine (YOH) reinstates drug seeking in rats. The present experiments investigated whether repeated exposure to YOH during extinction training affects the time-course of extinction and the magnitude of subsequent YOH- or footshock-induced reinstatement of cocaine seeking. Rats trained to self-administer cocaine were given five days of extinction training, during which they were injected with YOH (1.25 mg/kg, i.p.) either before or after daily extinction sessions. Following additional extinction training in the absence of YOH, animals were tested for reinstatement to a YOH (1.25 mg/kg, i.p.) or footshock (20 min, intermittent, 0.9 mA per 0.5 s shock) challenge. Animals injected with YOH before daily extinction sessions showed an attenuated rate of extinction, relative to control animals. Following additional extinction training in the absence of YOH treatment, these same animals showed a marked attenuation of YOH-induced reinstatement of cocaine seeking. YOH treatment during extinction did not, however, affect the magnitude of reinstatement induced by footshock. These findings demonstrate that repeated exposure to a stressor during extinction training can modulate the processes governing extinction learning and the subsequent reinstatement of drug seeking induced by that stressor.