Patients with depression often suffer from cognitive impairments that contribute to disease burden. We used social defeat-induced persistent stress (SDPS) to induce a depressive-like state in rats and then studied long-lasting memory deficits in the absence of acute stressors in these animals. The SDPS rat model showed reduced short-term object location memory and maintenance of long-term potentiation (LTP) in CA1 pyramidal neurons of the dorsal hippocampus. SDPS animals displayed increased expression of synaptic chondroitin sulfate proteoglycans in the dorsal hippocampus. These effects were abrogated by a 3-week treatment with the antidepressant imipramine starting 8 weeks after the last defeat encounter. Next, we observed an increase in the number of perineuronal nets (PNNs) surrounding parvalbumin-expressing interneurons and a decrease in the frequency of inhibitory postsynaptic currents (IPSCs) in the hippocampal CA1 region in SDPS animals. In vivo breakdown of the hippocampus CA1 extracellular matrix by the enzyme chondroitinase ABC administered intracranially restored the number of PNNs, LTP maintenance, hippocampal inhibitory tone, and memory performance on the object place recognition test. Our data reveal a causal link between increased hippocampal extracellular matrix and the cognitive deficits associated with a chronic depressive-like state in rats exposed to SDPS.

Alzheimer’s disease is caused by increased production or reduced clearance of amyloid-β, which results in the formation amyloid-β plaques and triggers a cascade of downstream events leading to progressive neurodegeneration. The earliest clinical symptoms of Alzheimer’s disease, i.e., memory loss, are however poorly understood from a molecular and cellular perspective. Here we used APPswe/PS1dE9 (APP/PS1) transgenic mice to study the early pre-pathological effects of increased amyloid-β levels on hippocampal synaptic plasticity and memory. Using an unbiased proteomics approach we show that the early increase in amyloid-β levels in APP/PS1 mice at three months of age coincides with a robust and significant upregulation of several protein components of the extracellular matrix in hippocampal synaptosome preparations. This increase in extracellular matrix levels occurred well before the onset of plaque formation and was paralleled by impairments in hippocampal long-term potentiation and contextual memory. Direct injection into the hippocampus of the extracellular matrix inactivating enzyme chondroitinase ABC restored both long-term potentiation and contextual memory performance. These findings indicate an important role for the extracellular matrix in causing early memory loss in Alzheimer’s disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-014-0076-z) contains supplementary material, which is available to authorized users.

Rationale The 5-choice serial reaction time task (5-CSRTT) is a widely used operant task for measuring attention and motor impulsivity in rodents. Training animals in this task requires an extensive period of daily operant sessions. Recently, a self-paced, automated version of this task has been developed for mice, which substantially reduces training time. Whether a similar approach is effective for rats is currently unknown. Objective Here, we tested whether attention and impulsivity can be assessed in rats with a self-paced version of the 5-CSRTT. Methods Operant boxes were connected to home-cages with tunnels. Two groups of rats self-paced their training by means of an automated script. The first group of animals was allowed unlimited access (UA) to start trials in the task; for the second group, trial availability was restricted to the first 2.5 h of the dark cycle (TR). Task parameter manipulations, such as variable inter-trial intervals and stimulus durations as well as pharmacological challenges with scopolamine, were tested to validate the task. Results Self-paced training took less than 1 week. Animals in the UA group showed higher levels of omissions compared with the TR group. In both protocols, variable inter-trial intervals increased impulsivity, and variable stimulus durations decreased attentional performance. Scopolamine affected cognitive performance in the TR group only. Conclusions Home-cage-based training of the 5-CSRTT in rats, especially the TR protocol, presents a valid and fast alternative for measuring attention and impulsivity.

Cornelisse LN, Van der Harst JE, Lodder JC, Baarendse PJ, Timmerman AJ, Mansvelder HD, Spruijt BM, Brussaard AB. Reduced 5-HT 1A -and GABA B receptor function in dorsal raphé neurons upon chronic fluoxetine treatment of socially stressed rats. J Neurophysiol 98: 196 -204, 2007. First published April 25, 2007; doi:10.1152/jn.00109.2007. Autoinhibitory serotonin 1A receptors (5-HT 1A ) in dorsal raphé nucleus (DRN) have been implicated in chronic depression and in actions of selective serotonin reuptake inhibitors (SSRI). Due to experimental limitations, it was never studied at single-cell level whether changes in 5-HT 1A receptor functionality occur in depression and during SSRI treatment. Here we address this question in a social stress paradigm in rats that mimics anhedonia, a core symptom of depression. We used whole cell patch-clamp recordings of 5-HT-and baclophen-induced G-proteincoupled inwardly rectifying potassium (GIRK) currents as a measure of 5-HT 1A -and GABA B receptor functionality. 5-HT 1A -and GABA B receptor-mediated GIRK-currents were not affected in socially stressed rats, suggesting that there was no abnormal (auto)inhibition in the DRN on social stress. However, chronic fluoxetine treatment of socially stressed rats restored anticipatory behavior and reduced the responsiveness of 5-HT 1A receptor-mediated GIRK currents. Because GABA B receptor-induced GIRK responses were also suppressed, fluoxetine does not appear to desensitize 5-HT 1A receptors but rather one of the downstream components shared with GABA B receptors. This fluoxetine effect on GIRK currents was also present in healthy animals and was independent of the animal's "depressed" state. Thus our data show that symptoms of depression after social stress are not paralleled by changes in 5-HT 1A receptor signaling in DRN neurons, but SSRI treatment can alleviate these behavioral symptoms while acting strongly on the 5-HT 1A receptor signaling pathway. 1995;Pejchal et al. 2002;Shen et al. 2002;Subhash et al. 2000). Although it remains unclear by which mechanism SSRIs exert their antidepressant action, there is a clear relation between reduced 5-HT1 A receptor function and increased 5-HT levels in DRN innervated forebrain areas after SSRI treatment in rodents. If SSRIs are acutely applied, locally enhanced 5-HT levels in the DRN inhibit serotonernergic neurons through activation of the 5-HT1 A autoreceptor. This results in decreased 5-HT release in the projection areas (Artigas et al. 1996b). However, after chronic SSRI treatment, 5-HT1 A receptors are desensitized, and firing of DRN cells is restored resulting in increased 5-HT levels in the frontal cortex (Artigas et al. 1996b;Bel and Artigas 1993). Co-application of 5-HT1 A receptor antagonists appears to prevent the initial decrease of 5-HT release in the forebrain during SSRI treatment and may accelerate antidepressant responses in patients (Artigas et al. 1996b;Blier et al. 1998).These studies suggest a role for DRN 5-HT1 A autoreceptors in etiology of depression as well as in ...