Astrocyte control of glutamatergic activity: Downstream effects on serotonergic function and emotional behavior.

Major depressive disorder (MDD) is a leading cause of disability worldwide, with a poorly known pathophysiology and sub-optimal treatment, based on serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors. We review existing theories on MDD, paying special attention to the role played by the ventral anterior cingulate cortex (vACC) or its rodent equivalent, infralimbic cortex (IL), which tightly control the activity of brainstem monoamine neurons (including raphe 5-HT neurons) via descending afferents. Further, astrocytes regulate excitatory synapse activity via glutamate reuptake through astrocytic transporters EAAT1 and EAAT2 (GLAST and GLT-1 in rodents), and alterations of astrocyte number/function have been reported in MDD patients and suicide victims. We recently assessed the impact of reducing GLAST/GLT-1 function in IL on emotional behavior and serotonergic function in rodents. The acute pharmacological blockade of GLT-1 with dihydrokainate (DHK) in rat IL evoked an antidepressant-like effect mediated by local AMPA-R activation and a subsequent enhancement of serotonergic function. No effects were produced by DHK microinfusion in prelimbic cortex (PrL). In the second model, a moderate small interfering RNAs (siRNA)-induced reduction of GLAST and GLT-1 expression in mouse IL markedly increased local glutamatergic neurotransmission and evoked a depressive-like phenotype (reversed by citalopram and ketamine), and reduced serotonergic function and BDNF expression in cortical/hippocampal areas. As for DHK, siRNA microinfusion in PrL did not evoke behavioral/neurochemical effects. Overall, both studies support a critical role of the astrocyte-neuron communication in the control of excitatory neurotransmission in IL, and subsequently, on emotional behavior, via the downstream associated changes on serotonergic function.

Avoid jumping to conclusions under uncertainty in Obsessive Compulsive Disorder.

High levels of intolerance of uncertainty (IU) could contribute to abnormal decision making in uncertain situations. Patients with Obsessive Compulsive Disorder (OCD) often report high IU, indecisiveness and the need to seek greater certainty before making decisions. The Beads task is a commonly used task assessing the degree of information gathering prior to making a decision and so would be predicted to show impairments in OCD patients. Results to date have found mixed support for this, possibility due to methodological issues. Here, a group of OCD patients (n = 50) with no comorbidities was compared with age, gender, and verbal-IQ matched controls (n = 50) on the most commonly used version of the Beads task. An independent sample of healthy volunteers with high versus low OC symptoms, and high versus low IU were also assessed (n = 125). There was no evidence that patients with OCD differed from control volunteers in the degree of information gathering prior to making a decision. Medication status and age did not appear to mediate performance. Similarly, there were no association in healthy volunteers between task performance and OC or IU characteristics. Additional measures examining the degree of certainty initially showed support for greater uncertainty in patients, but this was due to deviations from task instructions in a subset of patients. We conclude that despite the large sample size and good matching between groups, the Beads task in its most widely used form is not a useful measure of IU or of information gathering in OCD. The results argue against a robust behavioural difference in OCD when compared to controls. Recommendations for future studies employing the task are discussed.

Shifting the balance between goals and habits: Five failures in experimental habit induction.

Habits are repetitive behaviors that become ingrained with practice, routine, and repetition. The more we repeat an action, the stronger our habits become. Behavioral and clinical neuroscientists have become increasingly interested in this topic because habits may contribute to aspects of maladaptive human behavior, such as compulsive behavior in psychiatry. Numerous studies have demonstrated that habits can be induced in otherwise healthy rats by simply overtraining stimulus-response behaviors. However, despite growing interest in this topic and its application to psychiatry, a similar body of work in humans is absent. Only a single study has been published in humans that shows the effect of extensive training on habit expression. Here, we report five failed attempts to demonstrate that overtraining instrumental behavior leads to the development of inflexible habits in humans, using variants of four previously published outcome devaluation paradigms. Extensive training did not lead to greater habits in two versions of an avoidance learning task, in an appetitive slips-of-action task, or in two independent attempts to replicate the original demonstration. The finding that these outcome devaluation procedures may be insensitive to duration of stimulus-response training in humans has implications for prior work in psychiatric populations. Specifically, it converges with the suggestion that the failures in outcome devaluation in compulsive individuals reflect dysfunction in goal-directed control, rather than overactive habit learning. We discuss why habits are difficult to experimentally induce in healthy humans, and the implications of this for future research in healthy and disordered populations. (PsycINFO Database Record

Serotonergic mechanisms involved in antidepressant-like responses evoked by GLT-1 blockade in rat infralimbic cortex.

Novel fast-acting antidepressant strategies, such as ketamine and deep brain stimulation, enhance glutamatergic neurotransmission in medial prefrontal cortex (mPFC) regions via AMPA receptor (AMPA-R) activation. We recently reported that the regionally-selective blockade of the glial glutamate transporter-1 (GLT-1) by dihydrokainic acid (DHK) microinfusion in rat infralimbic cortex (IL), the most ventral part of the mPFC, evoked immediate (10 min) antidepressant-like responses, which involved AMPA-R activation and were associated to increased serotonin (5-hydroxytryptamine, 5-HT) release. Given the reciprocal connectivity between the mPFC and the serotonergic dorsal raphe nucleus (DR), here we examined the serotoninergic mechanisms involved in the reported antidepressant-like responses of DHK microinfusion. First, we show that antidepressant-like responses evoked by IL application of DHK and citalopram are mediated by local 5-HT1A receptors (5-HT1A-R), since they are cancelled by previous IL WAY100635 microinfusion. Second, IL DHK microinfusion increases excitatory inputs onto DR, as shown by an increased glutamate and 5-HT release in DR and by a selective increase of c-Fos expression in DR 5-HT neurons, not occurring in putative GABAergic neurons. This view is also supported by an increased 5-HT release in ventral hippocampus following IL DHK microinfusion. Interestingly, antidepressant-like responses evoked by IL DHK lasted for 2 h and could be prolonged for up to 24 h by attenuating self-inhibitory effects via 5-HT1A autoreceptors. In contrast, the antidepressant-like effects of S-AMPA microinfusion in IL were short-lasting. Together, our results further support a prominent role of the IL-DR pathway and of ascending 5-HT pathways in mediating antidepressant-like responses evoked by glutamatergic mechanisms.

Differential Patterns of Subcortical Activity Evoked by Glial GLT-1 Blockade in Prelimbic and Infralimbic Cortex: Relationship to Antidepressant-Like Effects in Rats.

Background: Glutamatergic neurotransmission has emerged as a novel target in antidepressant drug development, with a critical role of the ventral anterior cingulate cortex. We recently reported that blockade of the astrocytic glutamate transporter GLT-1 with dihydrokainic acid in infralimbic cortex (rodent equivalent of ventral anterior cingulate cortex), but not in the adjacent prelimbic cortex, evoked robust antidepressant-like effects through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor activation and increased serotonin release. Methods: 2-deoxy-2-[18F]-fluoro-D-glucose-positron emission tomography and computed tomography in 36 male Wistar rats microinfused bilaterally in prelimbic cortex or infralimbic cortex with dihydrokainic acid or vehicle. Results: Dihydrokainic acid microinfusion in infralimbic cortex and prelimbic cortex evoked dramatically different regional patterns of subcortical activity. In infralimbic cortex, dihydrokainic acid selectively affected midbrain areas, whereas in prelimbic cortex it affected the basal ganglia, the thalamus, and both superior and inferior colliculi. Conclusions: These results highlight the differential connectivity of infralimbic and prelimbic cortex with subcortical brain regions and support the involvement of infralimbic cortex-midbrain pathway in the antidepressant-like effects of dihydrokainic acid.