Regionally selective requirement for D1-D5 dopaminergic neurotransmisson in the medial prefrontal cortex in object-in-place associative recognition memorty:dopamine and object-in-place memory

Object-in-place (OiP) memory is critical for remembering the location in which an object was last encountered and depends conjointly on the medial prefrontal cortex, perirhinal cortex, and hippocampus. Here we examined the role of dopamine D(1)/D(5) receptor neurotransmission within these brain regions for OiP memory. Bilateral infusion of D(1)/D(5) receptor antagonists SCH23390 or SKF83566 into the medial prefrontal cortex, prior to memory acquisition, impaired OiP performance following a 5 min or 1 h delay. Retrieval was unaffected. Intraperirhinal or intrahippocampal infusions of SCH23390 had no effect. These results reveal a selective role for D(1)/D(5) receptors in the mPFC during OiP memory encoding

An investigation of the neural basis of associative recognition memory in the rat

Object-in-place (OIP) memory is a form of associative recognition memory which relies on the formation of an association between an object and the place in which such object was encountered. Existing evidence shows that OIP memory depends upon a circuit of neural regions which include the medial prefrontal cortex (mPFC), perirhinal cortex (PRH) and hippocampus (HPC). The aim of this thesis was to characterise further the cellular mechanisms which underlie OIP associative memory in the rat. Several lines of research have shown that mPFC, PRH and HPC receive a substantial dopaminergic projection and that in these areas dopamine plays a critical role in modulating plasticity and memory processes. In the first part of this thesis the role of dopamine neurotransmission within mPFC, PRH and HPC for OIP memory was investigated. Guide cannulae were implanted in the regions of interest to allow local infusion of the selective dopamine D1 receptor antagonist SCH23390 and OIP memory was tested using a spontaneous OlP memory task. Oopaminergic neurotransmission through D1 receptors was found to be required in mPFC for acquisition, but not for consolidation or retrieval, of both short-term and long-term OlP memory. In contrast direct infusion of SCH23390 into PRH or HPC produced no impairment in memory. Further, a possible role of dopamine through D2 receptors was excluded, as intra-mPFC infusion of the D2 receptor antagonist eticlopride did not cause any impairment in the task. These results demonstrated that dopaminergic neurotransmission via 01 receptors was selectively involved in the acquisition of OIP memory in the mPFC. The next series of experiments investigated the synaptic plasticity mechanism underlying long-term (24 h) OIP memory within the mPFC. Local blockade of PKMzeta, a protein critical for LTP, through infusion of the selective inhibitor ZIP, impaired OIP memory performance either when infused prior the sample or 5 h before the test. an the contrary, infusion of the synthetic peptide GluR2-3Y, a molecule critical for LTO, either before the sample phase or 5 h before the test, did not show any memory impairment. These findings suggested that an LTP-like, rather than an LTO-like, mechanism occurs both during the encoding and the maintenance of OIP memory. The final series of experiments presented in this thesis aimed to investigate whether other brain regions, beyond mPFC, PRH or HPC, were involved in OlP associative recognition memory. Neuronal activity was measured through the differential expression of the immediate early genes c-fos and zif268, following presentation of novel or familiar arrangements of visual stimuli. However here were no significant differences in levels of neuronal activation following the presentation of novel and familiar stimuli in any of the areas analysed, a finding which may relate to procedural issues in the presentation of the visual stimuli.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Early memory formation disrupted by atypical PKC inhibitor ZIP in the medial prefrontal cortex but not hippocampus

Atypical isoforms of protein kinase C (aPKCs; particularly protein kinase M zeta: PKMζ) have been hypothesised to be necessary and sufficient for the maintenance of long-term potentiation (LTP) and long term memory by maintaining postsynaptic AMPA receptors via the GluR2 subunit. A myristoylated PKMζ pseudosubstrate peptide (ZIP) blocks PKMζ activity. We examined the actions of ZIP in medial prefrontal cortex (mPFC) and hippocampus in associative recognition memory in rats during early memory formation and memory maintenance. ZIP infusion in either hippocampus or mPFC impaired memory maintenance. However, early memory formation was impaired by ZIP in mPFC but not hippocampus; and blocking GluR2-dependent removal of AMPA receptors did not affect this impairment caused by ZIP in the mPFC. The findings indicate: (i) a difference in the actions of ZIP in hippocampus and medial prefrontal cortex, and (ii) a GluR2-independent target of ZIP (possibly PKCλ) in the mPFC during early memory formation

Diurnal Oscillation of Amygdala Clock Gene Expression and Loss of Synchrony in a Mouse Model of Depression

Background: Disturbances in circadian rhythm-related physiological and behavioral processes are frequently observed in depressed patients and several clock genes have been identified as risk factors for the development of mood disorders. However, the particular involvement of the circadian system in the pathophysiology of depression and its molecular regulatory interface is incompletely understood. Methods: A naturalistic animal model of depression based upon exposure to chronic mild stress was used to induce anhedonic behavior in mice. Micro-punch dissection was used to isolate basolateral amygdala tissue from anhedonic mice followed by quantitative real-time PCRbased analysis of gene expression. Results: Here we demonstrate that chronic mild stress-induced anhedonic behavior is associated with disturbed diurnal oscillation of the expression of Clock, Cry2, Per1, Per3, Id2, Rev-erb, Ror- and Ror- in the mouse basolateral amygdala. Clock gene desynchronization was accompanied by disruption of the diurnal expressional pattern of vascular endothelial growth factor A expression in the basolateral amygdala of anhedonic mice, also reflected in alterations of circulating vascular endothelial growth factor A levels. Conclusion: We propose that aberrant control of diurnal rhythmicity related to depression may indeed directly result from the illness itself and establish an animal model for the further exploration of the molecular mechanisms mediating the involvement of the circadian system in the pathophysiology of mood disorders.(VLID)458050

Annals of Medicine / Fluoxetine normalizes disrupted light-induced entrainment, fragmented ultradian rhythms and altered hippocampal clock gene expression in an animal model of high trait anxiety- and depression-related behavior

Introduction Disturbances of circadian rhythms are a key symptom of mood and anxiety disorders. Selective serotonin reuptake inhibitors (SSRIs) - commonly used antidepressant drugs - also modulate aspects of circadian rhythmicity. However, their potential to restore circadian disturbances in depression remains to be investigated.Materials and methods The effects of the SSRI fluoxetine on genetically based, depression-related circadian disruptions at the behavioral and molecular level were examined using mice selectively bred for high anxiety-related and co-segregating depression-like behavior (HAB) and normal anxiety/depression behavior mice (NAB).Results The length of the circadian period was increased in fluoxetine-treated HAB as compared to NAB mice while the number of activity bouts and light-induced entrainment were comparable. No difference in hippocampal Cry2 expression, previously reported to be dysbalanced in untreated HAB mice, was observed, while Per2 and Per3 mRNA levels were higher in HAB mice under fluoxetine treatment.Discussion The present findings provide evidence that fluoxetine treatment normalizes disrupted circadian locomotor activity and clock gene expression in a genetic mouse model of high trait anxiety and depression. An interaction between the molecular mechanisms mediating the antidepressant response to fluoxetine and the endogenous regulation of circadian rhythms in genetically based mood and anxiety disorders is proposed.P 27520-B27(VLID)314239

Fluoxetine normalizes disrupted light-induced entrainment, fragmented ultradian rhythms and altered hippocampal clock gene expression in an animal model of high trait anxiety- and depression-related behavior

<p><b>Introduction</b> Disturbances of circadian rhythms are a key symptom of mood and anxiety disorders. Selective serotonin reuptake inhibitors (SSRIs) - commonly used antidepressant drugs – also modulate aspects of circadian rhythmicity. However, their potential to restore circadian disturbances in depression remains to be investigated.</p> <p><b>Materials and methods</b> The effects of the SSRI fluoxetine on genetically based, depression-related circadian disruptions at the behavioral and molecular level were examined using mice selectively bred for high anxiety-related and co-segregating depression-like behavior (HAB) and normal anxiety/depression behavior mice (NAB).</p> <p><b>Results</b> The length of the circadian period was increased in fluoxetine-treated HAB as compared to NAB mice while the number of activity bouts and light-induced entrainment were comparable. No difference in hippocampal <i>Cry2</i> expression, previously reported to be dysbalanced in untreated HAB mice, was observed, while <i>Per2</i> and <i>Per3</i> mRNA levels were higher in HAB mice under fluoxetine treatment.</p> <p><b>Discussion</b> The present findings provide evidence that fluoxetine treatment normalizes disrupted circadian locomotor activity and clock gene expression in a genetic mouse model of high trait anxiety and depression. An interaction between the molecular mechanisms mediating the antidepressant response to fluoxetine and the endogenous regulation of circadian rhythms in genetically based mood and anxiety disorders is proposed.</p

Scientific Reports / STAT3 controls IL6-dependent regulation of serotonin transporter function and depression-like behavior

Experimental evidence suggests a role for the immune system in the pathophysiology of depression. A specific involvement of the proinflammatory cytokine interleukin 6 (IL6) in both, patients suffering from the disease and pertinent animal models, has been proposed. However, it is not clear how IL6 impinges on neurotransmission and thus contributes to depression. Here we tested the hypothesis that IL6-induced modulation of serotonergic neurotransmission through the STAT3 signaling pathway contributes to the role of IL6 in depression. Addition of IL6 to JAR cells, endogenously expressing SERT, reduced SERT activity and downregulated SERT mRNA and protein levels. Similarly, SERT expression was reduced upon IL6 treatment in the mouse hippocampus. Conversely, hippocampal tissue of IL6-KO mice contained elevated levels of SERT and IL6-KO mice displayed a reduction in depression-like behavior and blunted response to acute antidepressant treatment. STAT3 IL6-dependently associated with the SERT promoter and inhibition of STAT3 blocked the effect of IL6 in-vitro and modulated depression-like behavior in-vivo. These observations demonstrate that IL6 directly controls SERT levels and consequently serotonin reuptake and identify STAT3-dependent regulation of SERT as conceivable neurobiological substrate for the involvement of IL6 in depression.(VLID)491089