Allostatic load, adverse childhood experiences, executive functions, and BMI status in adolescents and young adults.

OBJECTIVES: Chronic stress induces preclinical changes in the metabolic, cardiovascular, and immune systems. This phenomenon, known as allostatic load (AL), can impair executive functions (EF), which may be even more affected in individuals with excess weight due to their characteristic inflammatory state and cardiometabolic changes. Adverse childhood experiences (ACEs) contribute to AL and may influence executive functioning presumably via alterations within the hypothalamic-pituitary axis, including epigenetic modifications. We assess the relationship between AL and EF in youth with and without excess weight, and the effect ACEs on executive functioning. METHODS: One hundred eighty-two adolescents and young adults (85 with normal weight and 97 with overweight/obesity; 10-21 years) were recruited. The estimated AL index included the following: systolic and diastolic blood pressure, glycated hemoglobin, high- and low-density lipoprotein cholesterol, triglycerides, high-sensitivity C-reactive protein, fibrinogen, and cortisol. ACEs were measured using the Juvenile Victimization Questionnaire. The neuropsychological evaluation included the assessment of inhibition, working memory, and cognitive flexibility processes. RESULTS: AL was not significantly associated with executive functioning, and this relationship did not depend on body-weight status. ACEs, available for 57 of 182 participants, were significantly associated with poorer executive functioning. CONCLUSIONS: Our study shows that AL is not associated with executive functioning in adolescents and young adults. Since the current sample was young, we hypothesize that a longer exposure to AL might be required for its negative effects to surface. Nevertheless, exposure to early adversity seems to be associated with poorer executive functioning in youth.

From the reward network to whole-brain metrics: structural connectivity in adolescents and young adults according to body mass index and genetic risk of obesity.

BACKGROUND: Obesity is a multifactorial condition. Genetic variants, such as the fat mass and obesity related gene (FTO) polymorphism, may increase the vulnerability of developing obesity by disrupting dopamine signaling within the reward network. Yet, the association of obesity, genetic risk of obesity, and structural connectivity of the reward network in adolescents and young adults remains unexplored. We investigate, in adolescents and young adults, the structural connectivity differences in the reward network and at the whole-brain level according to body mass index (BMI) and the FTO rs9939609 polymorphism. METHODS: One hundred thirty-two adolescents and young adults (age range: [10, 21] years, BMI z-score range: [-1.76, 2.69]) were included. Genetic risk of obesity was determined by the presence of the FTO A allele. Whole-brain and reward network structural connectivity were analyzed using graph metrics. Hierarchical linear regression was applied to test the association between BMI-z, genetic risk of obesity, and structural connectivity. RESULTS: Higher BMI-z was associated with higher (B = 0.76, 95% CI = [0.30, 1.21], P = 0.0015) and lower (B = -0.003, 95% CI = [-0.006, -0.00005], P = 0.048) connectivity strength for fractional anisotropy at the whole-brain level and of the reward network, respectively. The FTO polymorphism was not associated with structural connectivity nor with BMI-z. CONCLUSIONS: We provide evidence that, in healthy adolescents and young adults, higher BMI-z is associated with higher connectivity at the whole-brain level and lower connectivity of the reward network. We did not find the FTO polymorphism to correlate with structural connectivity. Future longitudinal studies with larger sample sizes are needed to assess how genetic determinants of obesity change brain structural connectivity and behavior.

Body mass index, systemic inflammation and cognitive performance in adolescents: A cross-sectional study.

BACKGROUND: Excessive body weight has been related to lower cognitive performance. One of the mechanisms through which excess body weight may affect cognition is inflammation. HYPOTHESIS: Our hypothesis is that both body mass index (BMI) and circulating levels of inflammatory biomarkers will be negatively related to cognitive performance. DESIGN: Cross-sectional study. SETTING: Users of the public health centres of the Consorci Sanitari de Terrassa (Terrassa, Spain) between 2010 and 2017 aged 12-21 years. PARTICIPANTS: One hundred and five adolescents (46 normoweight, 18 overweight, 41 obese). MEASUREMENTS: Levels of high sensitivity C-reactive protein, interleukin 6, tumour necrosis factor α (TNFα) and fibrinogen were determined from blood samples. Cognitive performance was evaluated and six cognitive composites were obtained: working memory, cognitive flexibility, inhibitory control, decision-making, verbal memory, and fine motor speed. A single multivariate general lineal model was used to assess the influence of the four inflammatory biomarkers, as well as participants' BMI, sex, and age on the 6 cognitive indexes. RESULTS: An inverse relationship between BMI and inhibitory control (F = 5.688, p = .019; ß = -0.212, p = .031), verbal memory (F = 5.404, p = .022; ß = -0.255, p = .009) and fine motor speed (F = 9.038, p = .003; ß = -0.319, p = .001) was observed. Levels of TNFα and fibrinogen were inversely related to inhibitory control (F = 5.055, p = .027; ß = -0.226, p = .021) and verbal memory (F = 4.732, p = .032; ß = -0.274, p = .005), respectively. LIMITATIONS: The cross-sectional nature of the study, the use of cognitive tests designed for clinical purposes, and the use of BMI as a proxy for adiposity are limitations of our study that must be taken into account when interpreting results. CONCLUSIONS: Our data indicate that some components of executive functions, together with verbal memory, are sensitive to specific obesity-related inflammatory agents at early ages.

Beyond BMI: cardiometabolic measures as predictors of impulsivity and white matter changes in adolescents.

Obesity is characterized by cardiometabolic and neurocognitive changes. However, how these two factors relate to each other in this population is unknown. We tested the association that cardiometabolic measures may have with impulse behaviors and white matter microstructure in adolescents with and without an excess weight. One hundred and eight adolescents (43 normal-weight and 65 overweight/obesity; 11-19 years old) were medically and psychologically (Temperament Character Inventory Revised, Three-Factor Eating Questionnaire-R18, Conners' Continuous Performance Test-II, Stroop Color and Word Test, Wisconsin Card Sorting Test, Kirby Delay Discounting Task) evaluated. A subsample of participants (n = 56) underwent a brain magnetic resonance imaging acquisition. In adolescents, higher triglycerides and having a body mass index indicative of overweight/obesity predicted a more impulsive performance in Conners' Continuous Performance Test-II (higher commission errors). In addition, higher glucose and diastolic blood pressure values predicted increments in the Three-Factor Eating Questionnaire-R18 emotional eating scale. Neuroanatomically, cingulum fractional anisotropy showed a negative relationship with glycated hemoglobin. The evaluation of the neurocognitive differences associated with obesity, usually based on body mass index, should be complemented with cardiometabolic measures.

Discrimination of motor and sensorimotor effects of phencyclidine and MK-801: Involvement of GluN2C-containing NMDA receptors in psychosis-like models.

Non-competitive NMDA receptor (NMDA-R) antagonists like ketamine, phencyclidine (PCP) and MK-801 are routinely used as pharmacological models of schizophrenia. However, the NMDA-R subtypes, neuronal types (e.g., GABA vs. glutamatergic neurons) and brain regions involved in psychotomimetic actions are not fully understood. PCP activates thalamo-cortical circuits after NMDA-R blockade in reticular thalamic GABAergic neurons. GluN2C subunits are densely expressed in thalamus and cerebellum. Therefore, we examined their involvement in the behavioral and functional effects elicited by PCP and MK-801 using GluN2C knockout (GluN2CKO) and wild-type mice, under the working hypothesis that psychotomimetic effects should be attenuated in mutant mice. PCP and MK-801 induced a disorganized and meandered hyperlocomotion in both genotypes. Interestingly, stereotyped behaviors like circling/rotation, rearings and ataxia signs were dramatically reduced in GluN2CKO mice, indicating a better motor coordination in absence of GluN2C subunits. In contrast, other motor or sensorimotor (pre-pulse inhibition of the startle response) aspects of the behavioral syndrome remained unaltered by GluN2C deletion. PCP and MK-801 evoked a general pattern of c-fos activation in mouse brain (including thalamo-cortical networks) but not in the cerebellum, where they markedly reduced c-fos expression, with significant genotype differences paralleling those in motor coordination. Finally, resting-state fMRI showed an enhanced cortico-thalamic-cerebellar connectivity in GluN2CKO mice, less affected by MK-801 than controls. Hence, the GluN2C subunit allows the dissection of the behavioral alterations induced by PCP and MK-801, showing that some motor effects (in particular, motor incoordination), but not deficits in sensorimotor gating, likely depend on GluN2C-containing NMDA-R blockade in cerebellar circuits.

Dual 5-HT3 and 5-HT6 Receptor Antagonist FPPQ Normalizes Phencyclidine-Induced Disruption of Brain Oscillatory Activity in Rats.

Schizophrenia is a severe mental disorder featuring psychotic, depressive, and cognitive alterations. Current antipsychotic drugs preferentially target dopamine D2-R and/or serotonergic 5-HT2A/1A-R. They partly alleviate psychotic symptoms but fail to treat negative symptoms and cognitive deficits. Here we report on the putative antipsychotic activity of (1-[(3-fluorophenyl)sulfonyl]-4-(piperazin-1-yl)-1H-pyrrolo[3,2-c]quinoline dihydrochloride) (FPPQ), a dual serotonin 5-HT3-R/5-HT6-R antagonist endowed with pro-cognitive properties. FPPQ fully reversed phencyclidine-induced decrease of low-frequency oscillations in the medial prefrontal cortex of anaesthetized rats, a fingerprint of antipsychotic activity. This effect was mimicked by the combined administration of the 5-HT3-R and 5-HT6-R antagonists ondansetron and SB-399 885, respectively, but not by either drug alone. In freely moving rats, FPPQ countered phencyclidine-induced hyperlocomotion and augmentation of gamma and high-frequency oscillations in medial prefrontal cortex, dorsal hippocampus, and nucleus accumbens. Overall, this supports that simultaneous blockade of 5-HT3R and 5-HT6-R-like that induced by FPPQ-can be a new target in antipsychotic drug development.

Restrained Eating Is Associated with Lower Cortical Thickness in the Inferior Frontal Gyrus in Adolescents.

Some eating patterns, such as restrained eating and uncontrolled eating, are risk factors for eating disorders. However, it is not yet clear whether they are associated with neurocognitive differences. In the current study, we analyzed whether eating patterns can be used to classify participants into meaningful clusters, and we examined whether there are neurocognitive differences between the clusters. Adolescents (n = 108; 12 to 17 years old) and adults (n = 175, 18 to 40 years old) completed the Three Factor Eating Questionnaire, which was used to classify participants according to their eating profile using k means clustering. Participants also completed personality questionnaires and a neuropsychological examination. A subsample of participants underwent a brain MRI acquisition. In both samples, we obtained a cluster characterized by high uncontrolled eating patterns, a cluster with high scores in restrictive eating, and a cluster with low scores in problematic eating behaviors. The clusters were equivalent with regards to personality and performance in executive functions. In adolescents, the cluster with high restrictive eating showed lower cortical thickness in the inferior frontal gyrus compared to the other two clusters. We hypothesize that this difference in cortical thickness represents an adaptive neural mechanism that facilitates inhibition processes.

Clinical binge eating, but not uncontrolled eating, is associated with differences in executive functions: Evidence from meta-analytic findings.

INTRODUCTION: Binge eating disorder (BED) is a common psychiatric diagnosis characterized by the presence of episodes of loss of control over food consumption. Understanding the neurocognitive factors associated with binge eating pathology might help to design clinical strategies aimed at preventing or treating BED. However, results in the field are notably heterogeneous. In the current study, we aimed to establish whether binge eating behaviors (both at a clinical and at a non-clinical level) are associated with executive functions. METHODS: We performed a pre-registered meta-analysis to examine the link between executive functions, BED, and uncontrolled eating, a psychobiological construct closely associated with binge eating behaviors. Articles were searched on PubMed and the main exclusion criteria were lack of information about participants' age or sex distribution or adiposity measurements, studies performed in older populations (age > 65 years old) or studies including participants with purging symptoms. RESULTS: Relative to healthy controls, patients with BED showed lower performance in executive functions, with a small effect size. At the same time, uncontrolled eating patterns were not associated with differences in executive functions. Neither age nor body mass index (BMI) influenced these results. CONCLUSIONS: Our findings suggest that there is no association between performance in executive functions and variations along the non-clinical spectrum of binge eating behaviors. Small deficits in executive functions, however, seem to appear in individuals showing severe binge eating symptoms, that is, individuals meeting diagnostic criteria for BED. We speculate that the close links between BED and emotional distress could partly explain these results.

Involvement of NMDA receptors containing the GluN2C subunit in the psychotomimetic and antidepressant-like effects of ketamine.

Acute ketamine administration evokes rapid and sustained antidepressant effects in treatment-resistant patients. However, ketamine also produces transient perceptual disturbances similarly to those evoked by other non-competitive NMDA-R antagonists like phencyclidine (PCP). Although the brain networks involved in both ketamine actions are not fully understood, PCP and ketamine activate thalamo-cortical networks after NMDA-R blockade in GABAergic neurons of the reticular thalamic nucleus (RtN). Given the involvement of thalamo-cortical networks in processing sensory information, these networks may underlie psychotomimetic action. Since the GluN2C subunit is densely expressed in the thalamus, including the RtN, we examined the dependence of psychotomimetic and antidepressant-like actions of ketamine on the presence of GluN2C subunits, using wild-type and GluN2C knockout (GluN2CKO) mice. Likewise, since few studies have investigated ketamine's effects in females, we used mice of both sexes. GluN2C deletion dramatically reduced stereotyped (circling) behavior induced by ketamine in male and female mice, while the antidepressant-like effect was fully preserved in both genotypes and sexes. Despite ketamine appeared to induce similar effects in both sexes, some neurobiological differences were observed between male and female mice regarding c-fos expression in thalamic nuclei and cerebellum, and glutamate surge in prefrontal cortex. In conclusion, the GluN2C subunit may discriminate between antidepressant-like and psychotomimetic actions of ketamine. Further, the abundant presence of GluN2C subunits in the cerebellum and the improved motor coordination of GluN2CKO mice after ketamine treatment suggest the involvement of cerebellar NMDA-Rs in some behavioral actions of ketamine.

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.

Cyclin-Dependent Kinase 5 Dysfunction Contributes to Depressive-like Behaviors in Huntington's Disease by Altering the DARPP-32 Phosphorylation Status in the Nucleus Accumbens.

BACKGROUND: Depression is the most common psychiatric condition in Huntington's disease (HD), with rates more than twice those found in the general population. At the present time, there is no established molecular evidence to use as a basis for depression treatment in HD. Indeed, in some patients, classic antidepressant drugs exacerbate chorea or anxiety. Cyclin-dependent kinase 5 (Cdk5) has been involved in processes associated with anxiety and depression. This study evaluated the involvement of Cdk5 in the development and prevalence of depressive-like behaviors in HD and aimed to validate Cdk5 as a target for depression treatment. METHODS: We evaluated the impact of pharmacological inhibition of Cdk5 in depressive-like and anxiety-like behaviors in Hdh+/Q111 knock-in mutant mice by using a battery of behavioral tests. Biochemical and morphological studies were performed to define the molecular mechanisms acting downstream of Cdk5 activation. A double huntingtin/DARPP-32 (dopamine- and cAMP-regulated phosphoprotein 32) knock-in mutant mouse was generated to analyze the role of DARPP-32 in HD depression. RESULTS: We found that Hdh+/Q111 mutant mice exhibited depressive-like, but not anxiety-like, behaviors starting at 2 months of age. Cdk5 inhibition by roscovitine infusion prevented depressive-like behavior and reduced DARPP-32 phosphorylation at Thr75 in the nucleus accumbens. Hdh+/Q111 mice heterozygous for DARPP-32 Thr75Ala point mutation were resistant to depressive-like behaviors. We identified ß-adducin phosphorylation as a Cdk5 downstream mechanism potentially mediating structural spine plasticity changes in the nucleus accumbens and depressive-like behavior. CONCLUSIONS: These results point to Cdk5 in the nucleus accumbens as a critical contributor to depressive-like behaviors in HD mice by altering DARPP-32/ß-adducin signaling and disrupting the dendritic spine cytoskeleton.

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.

Social Memory and Social Patterns Alterations in the Absence of STriatal-Enriched Protein Tyrosine Phosphatase.

STriatal-Enriched protein tyrosine Phosphatase (STEP) is a neural-specific protein that opposes the development of synaptic strengthening and whose levels are altered in several neurodegenerative and psychiatric disorders. Since STEP is expressed in brain regions implicated in social behavior, namely the striatum, the CA2 region of the hippocampus, cortex and amygdala, here we investigated whether social memory and social patterns were altered in STEP knockout (KO) mice. Our data robustly demonstrated that STEP KO mice presented specific social memory impairment as indicated by the three-chamber sociability test, the social discrimination test, the 11-trial habituation/dishabituation social recognition test, and the novel object recognition test (NORT). This affectation was not related to deficiencies in the detection of social olfactory cues, altered sociability or anxiety levels. However, STEP KO mice showed lower exploratory activity, reduced interaction time with an intruder, less dominant behavior and higher immobility time in the tail suspension test than controls, suggesting alterations in motivation. Moreover, the extracellular levels of dopamine (DA), but not serotonin (5-HT), were increased in the dorsal striatum of STEP KO mice. Overall, our results indicate that STEP deficiency disrupts social memory and other social behaviors as well as DA homeostasis in the dorsal striatum.

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.

Defining the brain circuits involved in psychiatric disorders: IMI-NEWMEDS.

Despite the vast amount of research on schizophrenia and depression in the past two decades, there have been few innovative drugs to treat these disorders. Precompetitive research collaborations between companies and academic groups can help tackle this innovation deficit, as illustrated by the achievements of the IMI-NEWMEDS consortium.

Activation of AMPA Receptors Mediates the Antidepressant Action of Deep Brain Stimulation of the Infralimbic Prefrontal Cortex.

Although deep brain stimulation (DBS) has been used with success in treatment-resistant depression, little is known about its mechanism of action. We examined the antidepressant-like activity of short (1 h) DBS applied to the infralimbic prefrontal cortex in the forced swim test (FST) and the novelty-suppressed feeding test (NSFT). We also used in vivo microdialysis to evaluate the release of glutamate, γ-aminobutyric acid, serotonin, dopamine, and noradrenaline in the prefrontal cortex and c-Fos immunohistochemistry to determine the brain regions activated by DBS. One hour of DBS of the infralimbic prefrontal cortex has antidepressant-like effects in FST and NSFT, and increases prefrontal efflux of glutamate, which would activate AMPA receptors (AMPARs). This effect is specific of the infralimbic area since it is not observed after DBS of the prelimbic subregion. The activation of prefrontal AMPARs would result in a stimulation of prefrontal output to the brainstem, thus increasing serotonin, dopamine, and noradrenaline in the prefrontal cortex. Further, the activation of prefrontal AMPARs is necessary and sufficient condition for the antidepressant response of 1 h DBS.

PCP-based mice models of schizophrenia: differential behavioral, neurochemical and cellular effects of acute and subchronic treatments.

RATIONALE: N-methyl-D-aspartate receptor (NMDA-R) hypofunction has been proposed to account for the pathophysiology of schizophrenia. Thus, NMDA-R blockade has been used to model schizophrenia in experimental animals. Acute and repeated treatments have been successfully tested; however, long-term exposure to NMDA-R antagonists more likely resembles the core symptoms of the illness. OBJECTIVES: To explore whether schizophrenia-related behaviors are differentially induced by acute and subchronic phencyclidine (PCP) treatment in mice and to examine the neurobiological bases of these differences. RESULTS: Subchronic PCP induced a sensitization of acute locomotor effects. Spontaneous alternation in a T-maze and novel object recognition performance were impaired after subchronic but not acute PCP, suggesting a deficit in working memory. On the contrary, reversal learning and immobility in the tail suspension test were unaffected. Subchronic PCP significantly reduced basal dopamine but not serotonin output in medial prefrontal cortex (mPFC) and markedly decreased the expression of tyrosine hydroxylase in the ventral tegmental area. Finally, acute and subchronic PCP treatments evoked a different pattern of c-fos expression. At 1 h post-treatment, acute PCP increased c-fos expression in many cortical regions, striatum, thalamus, hippocampus, and dorsal raphe. However, the increased c-fos expression produced by subchronic PCP was restricted to the retrosplenial cortex, thalamus, hippocampus, and supramammillary nucleus. Four days after the last PCP injection, c-fos expression was still increased in the hippocampus of subchronic PCP-treated mice. CONCLUSIONS: Acute and subchronic PCP administration differently affects neuronal activity in brain regions relevant to schizophrenia, which could account for their different behavioral effects.

5-HT2A receptors are involved in cognitive but not antidepressant effects of fluoxetine.

The prefrontal cortex (PFC) plays a crucial role in cognitive and affective functions. It contains a rich serotonergic (serotonin, 5-HT) innervation and a high density of 5-HT receptors. Endogenous 5-HT exerts robust actions on the activity of pyramidal neurons in medial PFC (mPFC) via excitatory 5-HT2A and inhibitory 5-HT1A receptors, suggesting the involvement of 5-HT neurotransmission in cortical functions. However, the underlying mechanisms must be elucidated. Here we examine the role of 5-HT2A receptors in the processing of emotional and cognitive signals evoked by increasing the 5-HT tone after acute blockade of the 5-HT transporter. Fluoxetine (5-20mg/kg i.p.) dose-dependently reduced the immobility time in the tail-suspension test in wild-type (WT) and 5-HT2Aknockout (KO2A) mice, with non-significant differences between genotypes. Fluoxetine (10mg/kg i.p.) significantly impaired mice performance in the novel object recognition test 24h post-administration in WT, but not in KO2A mice. The comparable effect of fluoxetine on extracellular 5-HT in the mPFC of both genotypes suggests that presynaptic differences are not accountable. In contrast, single unit recordings of mPFC putative pyramidal neurons showed that fluoxetine (1.8-7.2mg/kg i.v.) significantly increased neuronal discharge in KO2A but not in WT mice. This effect is possibly mediated by an altered excitatory/inhibitory balance in the PFC in KO2A mice. Overall, the present results suggest that 5-HT2A receptors play a detrimental role in long-term memory deficits mediated by an excess 5-HT in PFC.

DWI and complex brain network analysis predicts vascular cognitive impairment in spontaneous hypertensive rats undergoing executive function tests.

The identification of biomarkers of vascular cognitive impairment is urgent for its early diagnosis. The aim of this study was to detect and monitor changes in brain structure and connectivity, and to correlate them with the decline in executive function. We examined the feasibility of early diagnostic magnetic resonance imaging (MRI) to predict cognitive impairment before onset in an animal model of chronic hypertension: Spontaneously Hypertensive Rats. Cognitive performance was tested in an operant conditioning paradigm that evaluated learning, memory, and behavioral flexibility skills. Behavioral tests were coupled with longitudinal diffusion weighted imaging acquired with 126 diffusion gradient directions and 0.3 mm(3) isometric resolution at 10, 14, 18, 22, 26, and 40 weeks after birth. Diffusion weighted imaging was analyzed in two different ways, by regional characterization of diffusion tensor imaging (DTI) indices, and by assessing changes in structural brain network organization based on Q-Ball tractography. Already at the first evaluated times, DTI scalar maps revealed significant differences in many regions, suggesting loss of integrity in white and gray matter of spontaneously hypertensive rats when compared to normotensive control rats. In addition, graph theory analysis of the structural brain network demonstrated a significant decrease of hierarchical modularity, global and local efficacy, with predictive value as shown by regional three-fold cross validation study. Moreover, these decreases were significantly correlated with the behavioral performance deficits observed at subsequent time points, suggesting that the diffusion weighted imaging and connectivity studies can unravel neuroimaging alterations even overt signs of cognitive impairment become apparent.

Acute 5-HT1A autoreceptor knockdown increases antidepressant responses and serotonin release in stressful conditions.

RATIONALE: Identifying the etiological factors in anxiety and depression is critical to develop more efficacious therapies. The inhibitory serotonin(1A) receptors (5-HT(1A)R) located on 5-HT neurons (autoreceptors) limit antidepressant responses and their expression may be increased in treatment-resistant depressed patients. OBJECTIVES: Recently, we reported that intranasal administration of modified small interference RNA (siRNA) molecules targeting 5-HT(1A)R in serotonergic neurons evoked antidepressant-like effects. Here we extended this finding using marketed siRNAs against 5-HT(1A)R (1A-siRNA) to reduce directly the 5-HT(1A) autoreceptor expression and evaluate its biological consequences under basal conditions and in response to stressful situations. METHODS: Adult mice were locally infused with vehicle, nonsense siRNA, and 1A-siRNA into dorsal raphe nucleus (DR). 5-HT(1A)R knockout mice (1A-KO) were also used. Histological approaches, in vivo microdialysis, and stress-related behaviors were performed to assess the effects of 5-HT(1A) autoreceptor knockdown. RESULTS: Intra-DR 1A-siRNA infusion selectively reduced 5-HT(1A)R mRNA and binding levels and canceled 8-OH-DPAT-induced hypothermia. Basal extracellular 5-HT in medial prefrontal cortex (mPFC) did not differ among treatments. However, 1A-siRNA-treated mice displayed less immobility in the tail suspension and forced swim tests, as did 1A-KO mice. This was accompanied by a greater increase in prefrontal 5-HT release during tail suspension test. Moreover, intra-DR 1A-siRNA infusion augmented the increase of extracellular 5-HT in mPFC evoked by fluoxetine, up to the level in 1A-KO mice. CONCLUSION: Together with our previous report, the present results indicate that acute suppression of 5-HT(1A) autoreceptor expression evokes robust antidepressant-like effects, likely mediated by an increased capacity of serotonergic neurons to release 5-HT in stressful conditions.