Anxiety exacerbates symptoms in various psychiatric disorders. In conditions such as obsessive-compulsive disorder (OCD) or Tourette syndrome, anxiety intensifies stereotypic and repetitive behaviors. Rodent self-grooming, a structured, repetitive innate behavior, serves as an effective rodent platform for studying these behaviors in neuropsychiatric research. Anxiety is also linked to altered functioning of the dopamine (DA) system, particularly within the substantia-nigra pars compacta (SNc), the main DA source to the dorsal striatum through the nigro-striatal pathway. Striatal modulation by DA signal also plays a complex role in repetitive behaviors and OCD-like symptoms, suggesting this system as linking anxiety to the induced exacerbation of repetitive behavior. In the present study, we observed several long-term effects of anxiety-inducing foot shock on grooming behavior. Recording single unit neuronal activity in the SNc revealed distinct response patterns related to grooming behavior with changes in the magnitude and timing following the shock treatment. Notably, DA neurons of different nigro-striatal pathways demonstrated different changes in different response pattern type units. DA neurons projecting to the dorsolateral striatum (DLS) showed increase, while those targeting the dorsomedial striatum (DMS) exhibited decrease in transient activity - suggesting a shift in cortico-striatal circuitry of behavioral control. These neural changes were correlated with the observed behavioral alterations following adversity. Furthermore, targeted stimulation of SNc DA neurons projecting to the DLS rescued the anxiety-induced behavioral effects, highlighting the critical role of the nigro-striatal pathway to the DLS in mediating the interaction between anxiety and repetitive behaviors, thus offering future direction for mitigation of relevant psychiatric symptoms.

Fear is a fundamental emotion that triggers rapid and automatic behavioral response. Fear is known to suppress reward-seeking behaviors, interrupt previous activities to prioritize defensive responses and lead to rapid switch to defensive reactions. Dopamine (DA) plays a complicated role in the choice and performance of actions and it has a potential interaction of innate actions with the presence of fear. Here, in a series of experiments we explore the role of the different DA striatal pathways in mediating grooming, an innate behavior comprised of a structured sequence of repetitive actions, with or without the presence of fear. Using chemogenetics, we specifically inhibited the DA pathways projecting to the dorsolateral striatum (DLS), dorsomedial striatum (DMS), and ventral striatum (VS), while mice were engaged in a behavioral paradigm inducing grooming during the presentation of a fear related cue. We found that fear related cues consistently reduced grooming proportions and shortened induced grooming bouts, regardless of DA manipulation, indicating prioritization of freezing behavior in fearful contexts. This also suggests that fear responses may be mediated through pathways independent of DA-based action selection. The role of DA, however, varies depending on the specific striatal pathway. Inhibiting DLS DA input delayed grooming initiation and reduced grooming when competing with freezing. In contrast, DMS DA input had no effect on grooming, while inhibition of VS mesolimbic DA input increased grooming proportions and duration. These findings underscore the distinct and sometimes opposing roles of different DA-striatal pathways in modulating innate behaviors. We discuss potential implications of this duality in DA function for both theoretical and clinical fields.

Innate defensive responses, though primarily instinctive, must also be highly adaptive to changes in risk assessment. However, adaptive changes can become maladaptive, following severe stress, as seen in posttraumatic stress disorder (PTSD). In a series of experiments, we observed long-term changes in innate escape behavior of male mice towards a previously non-threatening stimulus following an adverse shock experience manifested as a shift in the threshold of threat response. By recording neural activity in the superior colliculus (SC) while phototagging specific responses to afferents, we established the crucial influence of input arriving at the SC from the medial prefrontal cortex (mPFC), both directly and indirectly, on escape-related activity after adverse shock experience. Inactivating these specific projections during the shock effectively abolished the observed changes. Conversely, optogenetically activating them during encounters controlled escape responses. This establishes the necessity and sufficiency of those specific mPFC inputs into the SC for adverse experience related changes in innate escape behavior.

Innate defensive responses, while primarily instinctive, must also be flexible and highly adaptive to changes in risk assessment. As such, efficient innate escape behavior requires intricate processing to minimize reaction time while maximizing the success and adaptivity of the action. The superior colliculus (SC) is a subcortical sensorimotor integration center linking sensory threat information and escape. Adaptive changes in innate escape after learning could take a maladaptive turn after severe stress. Posttraumatic stress disorder (PTSD) is associated with long-term maladaptive changes after exposure to traumatic events, related to enhanced threat detection and reaction. Such long-term modifications are thought to involve the medial prefrontal cortex (mPFC), which is implicated in integrating learned emotional values into decisions that drive actions and behaviors. Here, in a series of experiments, we establish the crucial physiological role of specific mPFC neurons, exerting influence on the SC both directly and indirectly through the basal ganglia, in threat detection and reaction after adversity.

Post-traumatic stress disorder (PTSD) is a psychiatric disorder that afflicts many individuals. However, its molecular and cellular mechanisms remain largely unexplored. Here, we found PTSD susceptible mice exhibited significant up-regulation of alpha-Ca2+/calmodulin-dependent kinase II (αCaMKII) in the lateral amygdala (LA). Consistently, increasing αCaMKII in the LA not only caused PTSD-like behaviors such as impaired fear extinction and anxiety-like behaviors, but also attenuated N-methyl-D-aspartate receptor (NMDAR)-dependent long-term depression (LTD) at thalamo-lateral amygdala (T-LA) synapses, and reduced GluA1-Ser845/Ser831 dephosphorylation and a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) internalization. Suppressing the elevated αCaMKII to normal levels completely rescued both PTSD-like behaviors and the impairments in LTD, GluA1-Ser845/Ser831 dephosphorylation, and AMPAR internalization. Intriguingly, deficits in GluA1-Ser845/Ser831 dephosphorylation and AMPAR internalization were detected not only after impaired fear extinction, but also after attenuated LTD. Our results suggest that αCaMKII in the LA may be a potential molecular determinant of PTSD. We further demonstrate for the first time that GluA1-Ser845/Ser831 dephosphorylation and AMPAR internalization are molecular links between fear extinction and LTD.

Psychiatric conditions represent a highly heterogeneous group of disorders associated with chronic distress and a sharp decline in quality of life [...].

Shifting between goal-directed and habitual behaviors is essential for daily functioning. An inability to do so is associated with various clinical conditions, such as obsessive–compulsive disorder (OCD). Here we developed a new behavioral model in mice allowing us to produce and examine the development of different behaviors under goal-directed or habitual control. By using overtraining of instrumental associations between two levers and two rewards, and later devaluating one of the rewards, we differentiate and explore the motivational control of behaviors within the task which consequentially promotes what seems like excessive irrational behavior. Using our model, we found that the ability of instrumental behavior, to adapt to a change in the value of a known reward, is a function of practice. Once an instrumental action was practiced extensively it becomes habitual and, thus, under S–R control and could not be amended, not even when resulting in a noxious outcome. However, direct consummatory or Pavlovian actions, such as licking or checking, responds immediately to the change in value. This imbalance could render an instrumental behavior excessive and unresponsive to changes in outcome while the direct change in consumption implies that the change was in fact registered. This could suggest a system that, when out of balance, can create excessive behaviors, not adapting to an acknowledged change.

Animals constantly evaluate their environment in order to avoid potential threats and obtain reward in the form of food, shelter and social interactions. In order to appropriately respond to sensory cues from the environment, the brain needs to form and store multiple cue-outcome associations. These can then be used to form predictions of the valence of sounds, smells and other sensory inputs arising from the surroundings. However, these associations must be subject to constant update, as the environment can rapidly change. Failing to adapt to such change can be detrimental to survival. Several systems in the mammalian brain have evolved to perform these important behavioral functions. Among these systems, the amygdala and prefrontal cortex are prominent players. Although the amygdala has been shown to form strong cue-outcome associations, the prefrontal cortex is essential for modifying these associations through extinction and reversal learning, and synaptic plasticity occurring in the strong reciprocal connections between these structures is thought to underlie both adaptive and maladaptive learning. Here we review the synaptic organization of the amygdala-prefrontal circuit, and summarize the physiological and behavioral evidence for its involvement in appetitive and aversive learning.

Fear-related disorders are thought to reflect strong and persistent fear memories. The basolateral amygdala (BLA) and the medial prefrontal cortex (mPFC) form strong reciprocal synaptic connections that play a key role in acquisition and extinction of fear memories. While synaptic contacts of BLA cells onto mPFC neurons are likely to play a crucial role in this process, the BLA connects with several additional nuclei within the fear circuit that could relay fear-associated information to the mPFC, and the contribution of direct monosynaptic BLA-mPFC inputs is not yet clear. Here we establish an optogenetic stimulation protocol that induces synaptic depression in BLA-mPFC synapses. In behaving mice, optogenetic high-frequency stimulation of BLA inputs to mPFC interfered with retention of cued associations, attenuated previously acquired cue-associated responses in mPFC neurons and facilitated extinction. Our findings demonstrate the contribution of BLA inputs to mPFC in forming and maintaining cued fear associations.

The ability to switch flexibly between aversive and neutral behaviors based on predictive cues relies on learning driven by surprise or errors in outcome prediction. Surprise can occur as absolute value of the error (unsigned error) or its direction (signed errors; positive when something unexpected is delivered and negative when something expected is omitted). Signed and unsigned errors coexist in the brain and were associated with different systems, but how they interact and form across large networks remains vague. We recorded simultaneously in the amygdala and dorsal anterior cingulate cortex (dACC) of monkeys performing a reversal aversive-conditioning paradigm and quantified changes in interregional correlations when contingencies shift. We report that errors exist in different magnitudes and that they differentially develop at millisecond resolution. Our results support a model where unsigned errors first develop in the amygdala during successful learning and then propagate into the dACC, where signed errors develop and are distributed back to the amygdala.

The ability to distinguish danger from safety is crucial for survival. On the other hand, anxiety disorders can result from failures to dissociate safe cues from those that predict dangerous outcomes. The amygdala plays a major role in learning and signaling danger, and recently, evidence accumulates that it also acquires information to signal safety. Traditionally, safety is explored by paradigms that change the value of a previously dangerous cue, such as extinction or reversal; or by paradigms showing that a safe cue can inhibit responses to another danger-predicting cue, as in conditioned-inhibition. In real-life scenarios, many cues are never paired or tested with danger and remain neutral all along. A detailed study of neural responses to unpaired conditioned-stimulus (CS−) can therefore indicate whether information on safety-by-comparison is also acquired in the amygdala. We designed a multiple-CS study, with CS− from both visual and auditory modalities. Using discriminative aversive-conditioning, we find that responses in the primate amygdala develop for CS− of the same modality and of a different modality from that of the aversive CS+. Moreover, we find that responses are comparable in proportion, sign (increase/decrease), onset, and magnitude. These results indicate that the primate amygdala actively acquires signals about safety, and strengthen the hypothesis that failure in amygdala processing can result in failure to distinguish dangerous cues from safe ones and lead to maladaptive behaviors.

Functional abnormalities in the dorsal-anterior-cingulate-cortex (dACC) underlie anxiety disorders and specifically post-traumatic stress disorder (PTSD). Promising and common behavioral approaches have limited effectiveness and many subjects exhibit spontaneous recovery of fear, as also evident in animal models following extinction training. Here, we use low-frequency stimulation (LFS), a protocol shown to induce long-term depression, with the aim of affecting synaptic plasticity induced by fear acquisition and extinction. We use aversive conditioning of either tone or visual stimuli paired with an aversive air-puff to the eye in a trace-conditioning paradigm. We find that LFS in the nonhuman primate (Macaca fascicularis) dACC, when combined with extinction training, was successful in preventing spontaneous recovery of the memory 24–72 h following extinction. We simultaneously record single-units and local-field-potentials across the dACC, and show that LFS gradually depressed evoked responses. Moreover, this decrease in neural excitability predicted the successful reduction of overnight spontaneous recovery on a day-by-day basis. Finally, we show that this effect occurs when using either visual or auditory modality as the conditioned stimulus, and that the reduction was specific to the conditioned modality. Our results suggest that the primate dACC is actively involved in maintaining the original aversive memory, and propose that a combination of LFS with behavioral therapy might significantly improve treatment in severe cases.

The anti-compulsive effects of high and low frequency stimulation (LFS, HFS) of the entopeduncular nucleus and globus pallidus (the rat's equivalent, respectively, of the primate's internal and external segments of the globus pallidus) were assessed in the signal attenuation rat model of obsessive-compulsive disorder (OCD). HFS, but not LFS, of the two nuclei exerted an anti-compulsive effect, suggesting that HFS of either segment of the globus pallidus may provide an additional therapeutic strategy for OCD.

In the signal attenuation rat model of obsessive-compulsive disorder (OCD), 'compulsive' behavior is induced by attenuating a signal indicating that a lever-press response was effective in producing food. We have recently found that lesions to the rat orbitofrontal cortex (OFC) led to an increase in compulsive lever-pressing that was prevented by systemic administration of the selective serotonin reuptake inhibitor paroxetine, and paralleled by an increase in the density of the striatal serotonin transporter. This study further explored the interaction between the OFC, the striatum, and the serotonergic system in the production of compulsive lever-pressing. Experiment 1 revealed that OFC lesions decrease the content of serotonin, dopamine, glutamate, and GABA in the striatum. Experiment 2 showed that intrastriatal administration of paroxetine blocked OFC lesion-induced increased compulsivity, but did not affect compulsive responding in intact rats. Experiments 3 and 4 found that pre-training striatal lesions had no effect on compulsive lever-pressing, whereas post-training striatal inactivation exerted an anticompulsive effect. These results strongly implicate the striatum in the expression of compulsive lever-pressing in both intact and OFC-lesioned rats. Furthermore, the results support the possibility that in a subpopulation of OCD patients a primary pathology of the OFC leads to a dysregulation of the striatal serotonergic system, which is manifested in compulsive behavior, and that antiobsessional/anticompulsive drugs exerts their effects, in these patients, by normalizing the dysfunctional striatal serotonergic system.

Introduction The localization of cognitive domains can be achieved by functional imaging modalities such as fMRI, PET and MEG. It was recently shown that voxel-wise correlation between high resolution quantitative structural MRI (e.g. diffusion tensor imaging indices, DTI) and various behavioral measures allows brain localization of cognitive performance. This approach hypothesizes that inter-subject behavioral variability is manifested by morphological tissue variability leading to functional differences. The power of this methodology was demonstrated on the memory cognitive domain, where DTI indices extracted from the hippocampus, septum, fimbria and amygdala were shown to be in correlation with learning and memory abilities. In the present study we used the same technique to localize the behavioral manifestation of the signal attenuation (SA) rat model of obsessivecompulsive disorder (OCD). This model includes several phases. In the first phases the rats learn a basic relation between light, sound, lever pressing and collection of reward. During an extinction test, excessive lever-pressing is observed without the attempt to collect the reward. This behavior reflects the same behavioral disorder that is present in clinical OCD. In this study we used a voxel-wise approach to compare regional DTI indices differences between control and SA rats.

Serotonin 5-HT2A and 5-HT2C receptors have been implicated in the pathophysiology of obsessive-compulsive disorder (OCD) and in the mechanism mediating the anti-compulsive effects of serotonin reuptake inhibitors. Yet it is currently unclear whether activation or blockade of these receptors would have an anti-compulsive effect. The present study tested the effects of 5-HT2A and 5-HT2C activation and blockade in the signal attenuation rat model of OCD. In this model, 'compulsive' behaviour is induced by attenuating a signal indicating that a lever-press response was effective in producing food. Experiments1-4 revealed that systemic administration of the 5-HT2C antagonist RS 102221 (2 mg/kg) selectively decreases compulsive lever-pressing, whereas systemic administration of the 5-HT2A antagonist MDL11,939(0.2-5 mg/kg) or of the 5-HT2A/2C agonist DOI (0.05-5 mg/kg) did not have a selective effect on this behaviour. Experiments 5 and 6 found that systemic co-administration of DOI (0.5 mg/kg) withMDL11,939 (1 mg/kg) or with RS 102221 (2 mg/kg) had a non-selective effect on lever-press responding,with the former manipulation increasing and the latter manipulation decreasing lever-pressing. Finally,experiment 7 demonstrated that administration of RS 102221 directly into the orbitofrontal cortex also exerts an anti-compulsive effect. The results of these experiments suggest that blockade of 5-HT2Creceptors may have an anti-compulsive effect in OCD patients, and that this effect may be mediated by5-HT2C receptors within the orbitofrontal cortex.

Different lines of evidence point to dysfunction of basal ganglia-thalamocortical circuits in obsessive-compulsive disorder (OCD). It has been hypothesized that the circuits' dysfunction in OCD may be characterized by a relative under-activity of the indirect compared with the direct pathway within these circuits. The present study tested whether lesions of the subthalamic nucleus (STN), a major node of the indirect pathway, would affect compulsive behavior, using the signal attenuation rat model of OCD. In this model, compulsive lever-pressing is induced by the attenuation of an external signal of reward delivery; an attenuation that is hypothesized to simulate the deficient response feedback suggested to underlie obsessions and compulsions in patients with OCD. Rats sustaining lesions to the STN showed a selective increase in compulsive lever-pressing compared with sham-operated rats. A post mortem biochemical analysis revealed a decrease in serotonin content in the prelimbic and infralimbic cortices, caudate-putamen (but not nucleus accumbens), globus pallidus and substantia nigra-ventral tegmental area, as well as a decrease in dopamine content in the caudate-putamen in STN-lesioned compared with sham rats. A comparison to recent findings that lesions to the orbitofrontal cortex, which also result in a selective increase in compulsive lever-pressing, lead to a decrease in serotonin and dopamine content in the caudate-putamen suggests that there may be a final common pathway by which different brain pathologies may lead to a pro-compulsive state.

In recent years there have been several attempts to establish high frequency stimulation (HFS) as an additional treatment strategy for obsessive-compulsive disorder (OCD). Two studies reported that bilateral HFS of the subthalamic nucleus (STN) dramatically alleviated compulsions and improved obsessions in three patients with co-morbid Parkinson's disease and OCD. A recent study reported that HFS as well as pharmacological inactivation of the STN alleviate compulsive checking in the quinpirole rat model of OCD. As the quinpirole model is based on a dopaminergic manipulation, the aim of the present study was to test whether HFS and pharmacological inactivation of the STN exert an anti-compulsive effect also in the drug-naive brain, using the signal attenuation rat model of OCD. The main finding of the present study is that both HFS and pharmacological inactivation of the STN exerted an anti-compulsive effect, although the two manipulations differed in their effects on other behavioral measures. These findings support the possibility that HFS of the STN may provide an additional therapeutic strategy for OCD.