Expression Of Depressive-like Behaviors Research Articles

Excitation-inhibition imbalance in medial preoptic area circuits underlies chronic stress-induced depression-like states

Dysregulation of brain homeostasis is associated with neuropsychiatric conditions such as major depressive disorder. However, underlying neural-circuit mechanisms remain not well-understood. We show in mice that chronic restraint stress (CRS) and social defeat stress (SDS) are both associated with disruption of excitation (E)-inhibition (I) balance, with increased E/I ratios, in medial preoptic area (MPOA) circuits, but through affecting different neuronal types. CRS results in elevated activity in glutamatergic neurons, and their suppression mitigates CRS-induced depressive-like behaviors. Paraventricular hypothalamic input to these neurons contributes to induction but not expression of depressive-like behaviors. Their projections to ventral tegmental area and periaqueductal gray/dorsal raphe suppress midbrain dopaminergic and serotonergic activity, respectively, and mediate expression of divergent depressive-like symptoms. By contrast, SDS results in reduced activity of GABAergic neurons, and their activation alleviates SDS-induced depressive-like behaviors. Thus, E/I imbalance with relatively increased excitation in MPOA circuits may be a general mechanism underlying depression caused by different etiological factors.

Occlusion of dopamine-dependent synaptic plasticity in the prefrontal cortex mediates the expression of depressive-like behavior and is modulated by ketamine

Unpredictable chronic mild stress (CMS) is among the most popular protocols used to induce depressive-like behaviors such as anhedonia in rats. Differences in CMS protocols often result in variable degree of vulnerability, and the mechanisms behind stress resilience are of great interest in neuroscience due to their involvement in the development of psychiatric disorders, including major depressive disorder. Expression of depressive-like behaviors is likely driven by long-term alterations in the corticolimbic system and by downregulation of dopamine (DA) signaling. Although we have a deep knowledge about the dynamics of tonic and phasic DA release in encoding incentive salience and in response to acute/chronic stress, its modulatory action on cortical synaptic plasticity and the following implications on animal behavior remain elusive. Here, we show that the expression of DA-dependent synaptic plasticity in the medial prefrontal cortex (mPFC) is occluded in rats vulnerable to CMS, likely reflecting differential expression of AMPA receptors. Interestingly, such difference is not observed when rats are acutely treated with sub-anesthetic ketamine, possibly through the recruitment of dopaminergic nuclei such as the ventral tegmental area. In addition, by applying the synaptic activity sensor SynaptoZip in vivo, we found that chronic stress unbalances the synaptic drive from the infralimbic and prelimbic subregions of the mPFC toward the basolateral amygdala, and that this effect is counteracted by ketamine. Our results provide novel insights into the neurophysiological mechanisms behind the expression of vulnerability to stress, as well as behind the antidepressant action of ketamine.

A comparative analysis of kainate receptor GluK2 and GluK5 knockout mice in a pure genetic background

Kainate receptors (KARs) are members of the glutamate receptor family that regulate synaptic function in the brain. Although they are known to be associated with psychiatric disorders, how they are involved in these disorders remains unclear. KARs are tetrameric channels assembled from a combination of GluK1-5 subunits. Among these, GluK2 and GluK5 subunits are the major heteromeric subunits in the brain. To determine the functional similarities and differences between GluK2 and GluK5 subunits, we generated GluK2 KO and GluK5 KO mice on a C57BL/6N background, a well-characterized inbred strain, and compared their behavioral phenotypes. We found that GluK2 KO and GluK5 KO mice exhibited the same phenotypes in many tests, such as reduced locomotor activity, impaired motor function, and enhanced depressive-like behavior. No change was observed in motor learning, anxiety-like behavior, or sociability. Additionally, we identified subunit-specific phenotypes, such as reduced motivation toward their environment in GluK2 KO mice and an enhancement in the contextual memory in GluK5 KO mice. These results revealed that GluK2 and GluK5 subunits not only function in a coordinated manner but also have a subunit-specific role in regulating behavior. To summarize, we demonstrated subunit-specific and common behavioral effects of GluK2 and GluK5 subunits for the first time. Moreover, to the best of our knowledge, this is the first evidence of the involvement of the GluK5 subunit in the expression of depressive-like behavior and contextual memory, which strongly indicates its role in psychiatric disorders.

Astrocytic Epoxyeicosatrienoic Acid Signaling in the Medial Prefrontal Cortex Modulates Depressive-like Behaviors.

Major depressive disorder is the most common mental illness. Mounting evidence indicates that astrocytes play a crucial role in the pathophysiology of depression; however, the underlying molecular mechanisms remain elusive. Compared with other neuronal cell types, astrocytes are enriched for arachidonic acid metabolism. Herein, we observed brain-region-specific alterations of epoxyeicosatrienoic acid (EET) signaling, which is an arachidonic acid metabolic pathway, in both a mouse model of depression and postmortem samples from patients with depression. The enzymatic activity of soluble epoxide hydrolase (sEH), the key enzyme in EET signaling, was selectively increased in the mPFC of susceptible mice after chronic social defeated stress and was negatively correlated with the social interaction ratio, which is an indicator of depressive-like behavior. The specific deletion of Ephx2 (encode sEH) in adult astrocytes induced resilience to stress, whereas the impaired EET signaling in the mPFC evoked depressive-like behaviors in response to stress. sEH was mainly expressed on lysosomes of astrocytes. Using pharmacological and genetic approaches performed on C57BL/6J background adult male mice, we found that EET signaling modulated astrocytic ATP release in vitro and in vivo Moreover, astrocytic ATP release was required for the antidepressant-like effect of Ephx2 deletion in adult astrocytes. In addition, sEH inhibitors produced rapid antidepressant-like effects in multiple animal models of depression, including chronic social defeated stress and chronic mild stress. Together, our results highlight that EET signaling in astrocytes in the mPFC is essential for behavioral adaptation in response to psychiatric stress.SIGNIFICANCE STATEMENT Astrocytes, the most abundant glial cells of the brain, play a vital role in the pathophysiology of depression. Astrocytes secrete adenosine ATP, which modulates depressive-like behaviors. Notably, astrocytes are enriched for arachidonic acid metabolism. In the present study, we explored the hypothesis that epoxyeicosatrienoic acid signaling, an arachidonic acid metabolic pathway, modulates astrocytic ATP release and the expression of depressive-like behaviors. Our work demonstrated that epoxyeicosatrienoic acid signaling in astrocytes in the mPFC is essential for behavioral homeostatic adaptation in response to stress, and the extent of astrocyte functioning is greater than expected based on earlier reports.

Reduced vasopressin receptors activation mediates the anti-depressant effects of fluoxetine and venlafaxine in bulbectomy model of depression.

In response to stress, corticotropin releasing hormone (CRH) and vasopressin (AVP) are released from the hypothalamus, activate their receptors (CRHR1, CRHR2 or AVPr1b), and synergistically act to induce adrenocorticotropic hormone (ACTH) release from the anterior pituitary. Overstimulation of this system has been frequently associated with major depression states. The objective of the study is to assess the role of AVP and CRH receptors in fluoxetine and venlafaxine effects on the expression of depression-related behavior. In an animal model of depression (olfactory bulbectomy in mice, OB), we evaluated the effects of fluoxetine or venlafaxine (both 10 mg/kg/day) chronic administration on depression-related behavior in the tail suspension test. Plasma levels of AVP, CRH, and ACTH were determined as well as participation of their receptors in the expression of depression related-behavior and gene expression of AVP and CRH receptors (AVPr1b, CRHR1, and CRHR2) in the pituitary gland. The expression of depressive-like behavior in OB animals was reversed by treatment with both antidepressants. Surprisingly, OB-saline mice exhibited increased AVP and ACTH plasma levels, with no alterations in CRH levels when compared to sham mice. Chronic fluoxetine or venlafaxine reversed these effects. In addition, a significant increase only in AVPr1b gene expression was found in OB-saline. The antidepressant therapy used seems to be more likely related to a reduced activation of AVP rather than CRH receptors, since a positive correlation between AVP levels and depressive-like behavior was observed in OB animals. Furthermore, a full restoration of depressive behavior was observed in OB-fluoxetine- or venlafaxine-treated mice only when AVP was centrally administered but not CRH.

Effects of sex and deletion of neuropeptide Y2 receptors from GABAergic neurons on affective and alcohol drinking behaviors in mice.

A large literature has demonstrated that neuropeptide Y (NPY) regulates many emotional and reward-related behaviors via its primary receptors, Y1R and Y2R. Classically, NPY actions at postsynaptic Y1R decrease anxiety, depression, and alcohol drinking, while its actions at presynaptic Y2R produce the opposite behavioral phenotypes. However, emerging evidence suggests that activation of Y2R can also produce anxiolysis in a brain region and neurotransmitter system-dependent fashion. Further, numerous human and rodent studies have reported that females display higher levels of anxiety, depression, and alcohol drinking. In this study, we evaluated sex differences and the role of Y2R on GABAergic transmission in these behaviors using a novel transgenic mouse that lacks Y2R specifically in VGAT-expressing neurons (VGAT-Y2R knockout). First, we confirmed our genetic manipulation by demonstrating that Y2R protein expression was decreased and that a Y2R agonist could not alter GABAergic transmission in the extended amygdala, a limbic brain region critically implicated in the regulation of anxiety and alcohol drinking behaviors, using immunofluorescence and slice electrophysiology. Then, we tested male and female VGAT-Y2R knockout mice on a series of behavioral assays for anxiety, depression, fear, anhedonia, and alcohol drinking. We found that females displayed greater basal anxiety, higher levels of ethanol consumption, and faster fear conditioning than males, and that knockout mice exhibited enhanced depressive-like behavior in the forced swim test. Together, these results confirm previous studies that demonstrate higher expression of negative affective and alcohol drinking behaviors in females than males, and they highlight the importance of Y2R function in GABAergic systems in the expression of depressive-like behavior.

7. Transgenerational effects of LPS exposure on the expression of depressive-like behavior of mices rated by an experimental model of depression

There are considerable evidences that perinatal administration of lipopolysaccharide (LPS), a bacterial endotoxin, promotes persistent effects on development and behavior of offspring of mice. Mediators of inflammation can induce a depression-like state suggesting that infection and other inflammatory conditions could underlie depressive disorders. The present study evaluated three generations of offspring from dams of parental generation, selected to depressive response or not in the tail suspension test (TST), treated with LPS on gestational day 15, in order to check transgenerational effects on the offspring’s behavior. In each generation, the mice were tested to depressive effect or not in the TST. The results show that mice from mothers and fathers with depressive-like behavior have a higher percentage of offspring with the same behavior and the opposite was also observed in the healthy type ( p

Effects of early long-term treatment with antiepileptic drugs on development of seizures and depressive-like behavior in a rat genetic absence epilepsy model

Depression is most commonly associated with epilepsy. Recent reports have suggested a putative relationship between seizure development and onset of depressive behavior, whereas others proposed that two clinical entities might represent different neuropathologic aspects of the same neurologic disorder. The WAG/Rij rat absence epilepsy model has also been proposed as a suitable model to test antidepressant drugs. We previously reported on a long-term study of two antiepileptic drugs (AEDs) to assess their protective role in absence epileptogenesis. Here, we examined the effects of long-term treatment with several AEDs on absence seizure development and onset of depressive-like behavior in WAG/Rij rats at different ages, using a forced swimming test (FST). Animals were divided into one untreated control group and four test groups, given ethosuximide, levetiracetam, zonisamide, or carbamazepine. Electroencephalography (EEG) readings were recorded at 6.5 months of age. Ethosuximide-treated animals showed significant reductions in recorded spike-wave discharges (SWDs), and FST immobility time (IT) compared with untreated same age controls. However, zonisamide- and carbamazepine-treated animals had IT values similar to those of controls, but only zonisamide significantly decreased absence seizure development. Carbamazepine increased SWD incidence. Levetiracetam also protected against seizure development, while augmenting IT, suggesting a prodepressive effect. Although treatment with ethosuximide, levetiracetam, or zonisamide reduced appearance of SWDs in WAG/Rij rats, this was not generally linked to a reduced onset of depressive characteristics, as assessed by FST. Therefore, expression of depressive-like behavior seems unrelated to seizure control in this model. Some possible alternative explanations for the observed data are discussed.

Abnormal benzodiazepine receptor function in the depressive-like behavior of diabetic mice

We previously reported that streptozotocin (STZ)-induced diabetic mice exhibited depressive-like behavior in the tail suspension test. In this study, we examined the involvement of benzodiazepine receptor functions in this diabetes-induced depressive-like behavior in mice. STZ-induced diabetes significantly increased the duration of immobility without affecting spontaneous locomotor activity. This increase was dose-dependently and significantly suppressed by a benzodiazepine receptor antagonist, flumazenil (0.1–1 mg/kg, i.v.). However, flumazenil (0.1–1 mg/kg, i.v.) did not affect the duration of immobility in non-diabetic mice. Furthermore, flumazenil (1 mg/kg, i.v.) had no significant effect on spontaneous locomotor activity in either non-diabetic or diabetic mice. The benzodiazepine receptor inverse agonist methyl β-carboline-3-carboxylate (β-CCM; 0.03–0.3 mg/kg, i.v.) dose-dependently and significantly increased the duration of immobility in non-diabetic mice, but not in diabetic mice. β-CCM (0.3 mg/kg, i.v.) significantly suppressed spontaneous locomotor activity in non-diabetic mice, but not in diabetic mice. These results indicate that diabetic mice may have enhanced negative allosteric modulation by benzodiazepine receptor ligands, such as diazepam binding inhibitors, under stressful conditions, but not free-moving conditions, and this abnormal function of benzodiazepine receptors may cause, at least in part, the expression of depressive-like behavior in diabetic mice.