Thérèse M. Jay

The Prefrontal Cortex as a Key Target of the Maladaptive Response to Stress

Research on the detrimental effects of stress in the brain has mainly focused on the hippocampus. Because prefrontal cortex (PFC) dysfunction characterizes many stress-related disorders, we here analyzed the impact of chronic stress in rats on the integrity of the hippocampal–PFC pathway, monitored by behavioral and electrophysiological function and morphological assessment. We show that chronic stress impairs synaptic plasticity by reducing LTP induction in the hippocampal–PFC connection; in addition, it induces selective atrophy within the PFC and severely disrupts working memory and behavioral flexibility, two functions that depend on PFC integrity. We also demonstrate that short periods of stress exposure induce spatial reference memory deficits before affecting PFC-dependent tasks, thus suggesting that the impairment of synaptic plasticity within the hippocampus-to-PFC connection is of relevance to the stress-induced PFC dysfunction. These findings evidence a fundamental role of the PFC in maladaptive responses to stress and identify this area as a target for intervention in stress-related disorders.

TIMP-1 Abolishes MMP-9-Dependent Long-lasting Long-term Potentiation in the Prefrontal Cortex

BACKGROUNDnUnderstanding of the molecular mechanisms of prefrontal cortex (PFC) plasticity is important for developing new treatment strategies for mental disorders such as depression and schizophrenia. Long-term potentiation (LTP) is a valid model for synaptic plasticity. The extracellular proteolytic system composed of matrix metalloproteinases (MMPs) and their endogenous tissue inhibitors (TIMPs) has recently been shown to play major role in the hippocampal plasticity.nnnMETHODSnWe tested whether induction of hippocampal-prefrontal LTP results in accumulation of tissue inhibitor of MMP-1, TIMP-1 mRNA, in the PFC of rats and whether adenovirally driven overexpression of TIMP-1 affects LTP. Additional study of slices was done with a specific MMP-9 inhibitor.nnnRESULTSnThe TIMP-1 is induced in the rat medial PFC by stimuli evoking late LTP; its overexpression blocks the gelatinolytic activity of the MMP family; its overexpression before tetanization blocks late LTP in vivo; and MMP-9 inhibitor prevents late LTP in vitro.nnnCONCLUSIONSnWe suggest a novel extracellular mechanism of late LTP in the PFC, engaging TIMP-1-controlled proteolysis as an element of information integration. Our results may also be meaningful to an understanding of mental diseases and development of new treatment strategies that are based on extracellular mechanisms of synaptic plasticity.

D1 receptor modulation of memory retrieval performance is associated with changes in pCREB and pDARPP-32 in rat prefrontal cortex

We have recently shown a significant role of dopamine D(1) receptors in recognition and temporal order memory retrieval for objects in rodents [Hotte M, Naudon L, Jay TM. Modulation of recognition and temporal order memory retrieval by dopamine D(1) receptor in rats. Neurobiol Learn Mem 2005;84:85-92]. The present study investigates the signal transduction pathways underlying dopamine D(1) receptor modulation of retrieval performance in these memory tasks at different delays. We analyzed the level of phosphorylation of both CREB (cAMP response element binding protein) and DARPP-32 (dopamine and cAMP-regulated phosphoprotein, 32 kDa) in (1) the prefrontal cortex of rats that had performed the object recognition task, (2) the prefrontal and perirhinal cortices of rats that had performed the temporal order memory task for objects. For comparison, we explored the phosphorylation state of CREB and DARPP-32 in the prefrontal cortex, nucleus accumbens and hippocampus of rats having performed badly on the delayed spatial win-shift task after D(1) blockade. The improvement in recognition and temporal order memory performance at a 4h-delay was associated with an increased phosphorylation of both CREB and DARPP-32 in the prefrontal cortex of rats treated with the D(1) agonist SKF 81297. By contrast, the significant impairment of delayed spatial memory retrieval after administration of the selective D(1) antagonist SCH 23390 was associated with decreased phosphorylation of CREB and DARPP-32 in the prefrontal cortex. These results provide insight into molecular mechanisms involved in D(1) receptor-dependent modulation of short- versus long-term memory in prefrontal cortex where DARPP-32 in synergy with CREB may represent a pivotal role.

Effects of acute and chronic antidepressant treatments on memory performance: a comparison between paroxetine and imipramine

RationaleThe cognitive impairments apparent in many depressed patients appear to be alleviated by chronic treatments with antidepressants. However, evaluation of antidepressant treatments in rodents rarely includes investigation of their effects on cognitive performance.ObjectivesThe aim of this study was to investigate in rat the effects of paroxetine, a selective serotonin reuptake inhibitor antidepressant, and imipramine, a tricyclic antidepressant, on learning and memory in spatial and non-spatial tasks.Materials and methodsAdult male Sprague–Dawley rats weighing 230–250xa0g were used in two sets of experiments.ResultsSpatial working memory was first tested in a radial-arm maze using the delayed spatial win-shift task. During the course of a 10-day treatment, paroxetine-treated rats (10xa0mg/kg) did not show any deficit in memory performance. Conversely, imipramine-treated rats (10xa0mg/kg) made significantly more errors than controls. Secondly, we tested temporal order memory for objects. Rats received one injection or chronic injections (28xa0days) of imipramine (10xa0mg/kg), paroxetine (10xa0mg/kg) or saline. In contrast to controls, on the day after the acute injection, both imipramine- and paroxetine-treated rats were unable to discriminate the old from the recent objects. After chronic treatment, the imipramine-treated rats were unable to differentiate between the two objects, whereas paroxetine-treated rats, as controls, spent more time exploring the old one. When the delay before the test phase was increased to 4xa0h, controls could not discriminate the objects, whereas rats treated for 28xa0days with paroxetine were able to distinguish the old from the recent object.ConclusionsIn contrast to the persistent harmful effects of imipramine, chronic treatment with paroxetine does not alter spatial working memory performance and appears to improve temporal order memory performance.

Common efficacy of psychotropic drugs in restoring stress-induced impairment of prefrontal plasticity.

We recently Investigated the effects of stress on synaptic plasticity in the prefrontal cortex, namely the prelimbic area or the apparent homologue of the primate subgenual prefrontal cortex in humans where most of the hippocampal terminal fields are localized. Exposure to an acute stress causes a remarkable and long-lasting inhibition of long term potentiation (LTP) in the frontal cortex evoked by stimulation of hippocampal outflow and this impairment is prevented by the glucocorticoid receptor antagonist mifepristone. Thus, the frontal cortex is also a target for glucocorticoids Involved In the stress response. Current data show that antidepressants of various types,i.e., tianeptine and fluoxetine, at doses normally used In antidepressant testing, restore LTP Impaired by prior acute stress. Interestingly, dozapine administered in a similar way after stress rapidly reverses the stress-induced impairment of LTP at doses which do not affect LTP alone. This stress paradigm highlights comorbidity for both etiology and treatment of psychiatric disorders like depression and schizophrenia. Restoring appropriate cognitive functions in circuits associated with dysfunctions in coping with stress may be proposed as a new systems-level approach to drug discovery and development We are presently investigating the involvement of signalling molecules in producing these plastic changes.

Effect of antipsychotics on spontaneous hyperactivity and hypersensitivity to MK-801-induced hyperactivity in rats prenatally exposed to methylazoxymethanol

Exposure to methylazoxymethanol (MAM) at embryonic day 17 (E17) in the rat has been proposed to be a promising model for schizophrenia that mimics behavioural abnormalities and deficits in prefrontal cortex (PFC) networks. In this study, we investigated for the first time the effects of antipsychotics on abnormal behaviours observed in prenatally MAM-exposed rats. We first examined spontaneous and MK-801-induced locomotor activity in an open field in adult E17 MAM- or saline-exposed rats. Then, the effect of single injections of haloperidol, clozapine and risperidone was investigated in MAM- or sham-exposed rats on spontaneous and MK-801 (0.05u2009mg/kg)-induced hyperactivity. Risperidone more selectively counteracted the spontaneous hyperactivity in MAM than in sham rats, while haloperidol and clozapine induced similar effects on spontaneous locomotion in both groups. The main result of this study is that all the tested antipsychotics were more effective in attenuating the MK-801-induced hyperlocomotion in MAM than in sham rats. These findings further support the validity of E17 MAM exposure as a model for schizophrenia and add to its heuristic value in screening therapies for schizophrenia.

Limbic versus cognitive target for deep brain stimulation in treatment-resistant depression: accumbens more promising than caudate.

High-frequency deep brain stimulation (DBS) represents a major stake for treatment for treatment-resistant depression (TRD). We describe a preliminary trial of DBS of two potential brain targets in chronic TRD: the nucleus accumbens (Acb) and, in the event of failure, the caudate nucleus. Patients were followed for 6 months before surgery (M0). From M1 to M5, they underwent stimulation of the Acb target. PET scans allowed us to track metabolic modifications resulting from this stimulation. The caudate target of nonresponders was stimulated between M5 and M9. Patients then entered an extension phase, in which it was possible to adapt stimulation parameters and treatments. Six patients were included and four were operated on. At M5, none of the patients were either responders or remitters, but we did observe a decrease in Hamilton Depression Rating Scale (HDRS) scores. Three patients were switched to caudate stimulation, but no improvement was observed. During the extension phase, the Acb target was stimulated for all patients, three of whom exhibited a significant response. A decrease in glucose metabolism was observed after Acb stimulation, in the posterior cingulate gyrus, left frontal lobe, superior and medial gyrus, and bilateral cerebellum. An increase in metabolism was observed in the bilateral frontal lobe (superior gyrus), left frontal lobe (medial gyrus), and right limbic lobe (anterior cingulate gyrus). The results of this trial suggest that Acb is a more promising target than the caudate. NCT01569711.

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.

Anticonvulsive Effect of a Selective mGluR8 Agonist (S)‐3,4‐Dicarboxyphenylglycine (S‐3,4‐DCPG) in the Mouse Pilocarpine Model of Status Epilepticus

Summary:u2002 Purpose: We sought to investigate the anticonvulsive and neuroprotective effect of a selective metabotropic glutamate receptor 8 (mGluR8) agonist (S)‐3,4‐dicarboxyphenylglycines (S‐3,4‐DCPG) on pilocarpine‐induced status epilepticus (PISE) and subsequent loss of hilar neurons in the dentate gyrus after systemic (intravenous) or local (intracerebroventricular) administration. We compared the difference in granular cell responses after paired‐pulse stimulation of the perforant pathway and the sensitivity to local injection of S‐3,4‐DCPG into the stratum granulosum in the control and mice at 2 months after PISE.

White matter changes in microstructure associated with a maladaptive response to stress in rats

In today’s society, every individual is subjected to stressful stimuli with different intensities and duration. This exposure can be a key trigger in several mental illnesses greatly affecting one’s quality of life. Yet not all subjects respond equally to the same stimulus and some are able to better adapt to them delaying the onset of its negative consequences. The neural specificities of this adaptation can be essential to understand the true dynamics of stress as well as to design new approaches to reduce its consequences. In the current work, we employed ex vivo high field diffusion magnetic resonance imaging (MRI) to uncover the differences in white matter properties in the entire brain between Fisher 344 (F344) and Sprague–Dawley (SD) rats, known to present different responses to stress, and to examine the effects of a 2-week repeated inescapable stress paradigm. We applied a tract-based spatial statistics (TBSS) analysis approach to a total of 25 animals. After exposure to stress, SD rats were found to have lower values of corticosterone when compared with F344 rats. Overall, stress was found to lead to an overall increase in fractional anisotropy (FA), on top of a reduction in mean and radial diffusivity (MD and RD) in several white matter bundles of the brain. No effect of strain on the white matter diffusion properties was observed. The strain-by-stress interaction revealed an effect on SD rats in MD, RD and axial diffusivity (AD), with lower diffusion metric levels on stressed animals. These effects were localized on the left side of the brain on the external capsule, corpus callosum, deep cerebral white matter, anterior commissure, endopiriform nucleus, dorsal hippocampus and amygdala fibers. The results possibly reveal an adaptation of the SD strain to the stressful stimuli through synaptic and structural plasticity processes, possibly reflecting learning processes.