Place cells in the claustrum remap under NMDA receptor control.

Place cells are cells that exhibit location-dependent responses; they have mostly been studied in the hippocampus. Place cells have also been reported in the rat claustrum, an underexplored paracortical region with extensive corto-cortical connectivity. It has been hypothesised that claustral neuronal responses are anchored to cortical visual inputs. We show rat claustral place cells remap when visual inputs are eliminated from the environment, and that this remapping is NMDA-receptor-dependent. Eliminating visual input decreases claustral delta-band oscillatory activity, increases theta-band oscillatory activity, and increases simultaneously recorded visual cortical activity. We conclude that, like the hippocampus, claustral place field remapping might be mediated by NMDA receptor activity, and is modulated by visual cortical inputs.

The Antidepressant-Like Effects of a Clinically Relevant Dose of Ketamine Are Accompanied by Biphasic Alterations in Working Memory in the Wistar Kyoto Rat Model of Depression.

Major depressive disorder (MDD) is the leading cause of disability worldwide. The majority of antidepressant drugs require several weeks or months of treatment to demonstrate efficacy and a subset of patients are resistant to such interventions. Ketamine demonstrates rapid and long-lasting antidepressant effects in treatment resistant patients; however, side effects may limit its widespread clinical utility. The pharmaceutical industry is engaged in developing novel rapid-acting antidepressant drugs and the establishment of clinically relevant assays are needed to advance this process. Wistar Kyoto (WKY) rats are a valuable model of many of the characteristics of MDD and their resistance to selective serotonin reuptake inhibitors (SSRIs) in several behavioral paradigms emulates treatment resistance in clinical populations. Here, we confirmed the depressive-like phenotype of WKY rats in comparison to Sprague Dawley rats, characterized by increased immobility in the forced swim test, decreased locomotor activity and entries to the centre in the open field test, anhedonia in the female urine sniffing test and working memory deficits in the delayed non-match to position task. Single subcutaneous administration of 5 mg/kg ketamine in WKY rats mirrored the plasma exposure produced by the antidepressant dose in the clinic and rescued depressive-like behaviors. The same dose induced transient side effects, including decreased locomotor activity and reduced positive affect-associated vocalizations. Furthermore, ketamine acutely impaired working memory but induced pro-cognitive effects at a later time point. These data confirm the WKY rat as a preclinical model of depression. Ketamine's efficacy in recovering this depressive-like phenotype while inducing transient dissociative-like effects supports this as a translational model suitable for investigating novel antidepressant drugs.

Opioid modulation of depression: A focus on imaging studies.

Depression is the leading cause of disability worldwide, with over 300 million people affected. Almost all currently available antidepressant treatments target monoamine neurotransmitter systems and have a delayed onset of action up to several weeks that can be associated with low rates of treatment response. The endogenous opioid system has been identified as a potential target for the development of novel antidepressants due to its high opioid receptor concentrations in central limbic areas that are also implicated in physiological processes including regulation of mood and emotion. Genetic depletion, pharmacological manipulation, and preclinical models have been widely used to characterize the role of opioid transmission in depressive states. Neuroimaging studies have been carried out in clinical populations to investigate opioid transmission in mood and emotion in an attempt to identify those regional anatomical and functional brain changes that are associated with depression. Great insight has been provided into the cerebral structural and functional changes associated with depression but there remains a need to tie the functional theories of depression to anatomical localization and further neuroimaging studies are best placed to do this.

Potential roles for opioid receptors in motivation and major depressive disorder.

Deficits in motivation are at the core of many neuropsychiatric disorders, including major depressive disorder (MDD). Research in MDD has been heavily focused on anhedonia and depression or negative/positive symptoms of depression, with less research attention focused on the dysregulation of motivational processes. Opioid receptors are widely distributed throughout the brain, particularly in areas implicated in motivation, especially the striatum, nucleus accumbens, medial prefrontal cortex, hippocampus, ventral tegmental area, hypothalamus, and amygdala. Mu, kappa, and delta opioid receptors (MOR, KOR, and DOR, respectively) and their endogenous ligands play an essential role in the regulation of mood, reward processing, and motivated behavior. This review will highlight the impact of opioids in motivational behavior with a particular focus on depression. An understanding of the neurobiology and neural circuits subserving motivational behavior will facilitate treatment of disorders that comprise reward deficits.

Antidepressant-like effects of 3-carboxamido seco-nalmefene (3CS-nalmefene), a novel opioid receptor modulator, in a rat IFN-α-induced depression model.

Patients receiving the cytokine immunotherapy, interferon-alpha (IFN-α) frequently present with neuropsychiatric consequences and cognitive impairments. Patients (25-80%) report symptoms of depression, including, anhedonia, irritability, fatigue and impaired motivation. Our lab has previously demonstrated treatment (170,000IU/kg sc, 3 times per week for 4weeks) of the pro-inflammatory cytokine, IFN-α, induced a depressive phenotype in rats in the forced swim test (FST). Here, we examine the biological mechanisms underlying behavioral changes induced by IFN-α, which may be reflective of mechanisms underlying inflammation associated depression. We also investigate the potential of 3-carboxamido seco-nalmefene (3CS-nalmefene), a novel opioid modulator (antagonist at mu and partial agonist at kappa and delta opioid receptors in vitro), to reverse IFN-α induced changes. In vitro radioligand receptor binding assays and the [35S] GTPγS were performed to determine the affinity of 3CS-nalmefene for the mu, kappa and delta opioid receptors. IFN-α treatment increased circulating and central markers of inflammation and hypothalamic-pituitaryadrenal (HPA) axis activity (IL-6, IL-1ß and corticosterone) while increasing immobility in the FST, impairing of object displacement learning in the object exploration task (OET), and decreasing neuronal proliferation and brain-derived neurotrophic factor (BDNF) in the hippocampus. Treatment with 3CS-nalmefene (0.3mg/kg/sc twice per day, 3 times per week for 4weeks) prevented IFN-α-induced immobility in the FST and impaired object displacement learning. In addition, 3CS-nalmefene prevented IFN-α-induced increases in inflammation and hyperactivity of the HPA-axis, the IFN-α-induced reduction in both neuronal proliferation and BDNF expression in the hippocampus. Overall, these preclinical data would support the hypothesis that opioid receptor modulation is a relevant target for treatment of depression.

Exercise prevents IFN-α-induced mood and cognitive dysfunction and increases BDNF expression in the rat.

Aerobic exercise has marked effects on mood and cognition. Here, we used an interferon-alpha (IFN-α) induced depression model to evaluate the potential efficacy of chronic treadmill running on mood and cognition in the rat. IFN-α treatment induces behavioral deficits in the forced swim test (FST), open field test and object exploration task. Male han Wistar rats (n=8 per group, 3month old) were injected 3 times weekly with recombinant human IFN-α or saline (control) for 4weeks. One group was exercised 3 times (1h treadmill running) per week while the other remained sedentary. Animals were tested for anxiety- and depressive-like behavior in the open field test and FST. Spatial and recognition memory were examined by the object exploration task. Hippocampal and prefrontal cortex brain samples were harvested for analysis of brain-derived neurotrophic factor (BDNF). Treadmill running prevented IFN-α-induced decreased central arena exploration in the open field test and decreased immobility in the FST. IFN-α treated rats had impaired spatial memory in the object exploration task compared to saline controls, which was prevented by treadmill running. Further, treadmill running improved recognition memory in both saline and IFN-α treated rats. Treadmill running protected against IFN-α induced decreases in expression of BDNF in the hippocampus and prefrontal cortex. Aerobic exercise protects against IFN-α induced affective and cognitive dysfunction, which is associated with increased BDNF. Results could have implications for future treatments of depression.

Glial fibrillary acidic protein (GFAP) immunoreactivity correlates with cortical perfusion parameters determined by bolus tracking arterial spin labelling (bt-ASL) magnetic resonance (MR) imaging in the Wistar Kyoto rat.

Alterations in astrocyte number and function have been implicated in the pathophysiology of a number of psychiatric disorders. The development of magnetic resonance imaging (MRI) as a tool in the animal laboratory has enabled an investigation of the relationship between pathological and neuroimaging markers in animal models. However the physiological processes which underlie these markers and their role in mediating behavioural deficits is still poorly understood. Rodent models have provided us with important insights into physiological and cellular mechanisms which may mediate anxiety and depression-related behaviours. The Wistar-Kyoto (WKY) rat is a strain which endogenously expresses highly anxious and depressive-like behaviours and has previously been reported to exhibit alterations in immunoreactivity for the astrocytic marker glial fibrillary acidic protein (GFAP) in brain sub-regions relative to more stress resilient out-bred strains. Here we report that the depressive and anxiety-like behaviours exhibited by the WKY rat strain are associated with alterations in brain morphology including a decrease in hippocampal volume, coupled with reduced resting state frontal cortical perfusion as assessed by MR bolus tracking arterial spin labelling (bt-ASL) relative to the out-bred Wistar strain. Pre-limbic cortical GFAP immunoreactivity and astrocyte cell number were positively correlated with cortical blood perfusion in the WKY strain. These experiments provide a link between pathological and neuroimaging markers of aberrant astrocytic function and add validity to the WKY rat as a model for co-morbid anxiety and depression.

Characterisation of the antidepressant properties of nitric oxide synthase inhibitors in the olfactory bulbectomised rat model of depression.

Nitric oxide synthase (NOS) inhibitors possess antidepressant-like properties in preclinical tests and in the current investigation the brain penetrant NOS inhibitor N(ω)-nitro-L-arginine (l-NA) and the preferential inhibitor of neuronal NOS (nNOS) 1-(2-trifluoromethylphenyl) imidazole (TRIM) were assessed in the olfactory bulbectomised (OB) rat, a well-established animal model of depression. Magnetic resonance imaging (MRI) was employed to assess regional brain volumes, blood perfusion and T1 and T2 relaxometry times both with and without drug treatment. l-NA (10 mg/kg, once daily p.o. for 10 days) attenuated OB-related hyperactivity in the "open field" test in a comparable fashion to the tricyclic antidepressant imipramine (20 mg/kg, once daily p.o. for 14 days) indicative of an antidepressant-like response in the model. Treatment with TRIM (50 mg/kg, once daily s.c.) attenuated OB-related hyperactivity following 7 days of treatment when compared to vehicle treated controls. OB is associated with enlarged ventricular volume, increased periventicular perfusion and a decrease in T2 relaxation times in cortical and hippocampal regions, with enhanced perfusion and reduced T2 times attenuated by L-NA treatment. L-NA treatment was also associated with an increase in T1 relaxation times in limbic and cortical regions and found to reduce resting state hippocampal blood perfusion in OB animals. Behavioural observations are consistent with an antidepressant action of NOS inhibitors where associated changes in perfusion and T2 relaxation times may be related to the antidepressant action of L-NA in the model.

Deficits in LTP and recognition memory in the genetically hypertensive rat are associated with decreased expression of neurotrophic factors and their receptors in the dentate gyrus.

We have previously reported that a genetically hypertensive strain of Wistar rat (GH), is deficient in nerve growth factor (NGF) and Trk receptors in dentate gyrus and that these deficits are accompanied by impaired expression of long-term potentiation (LTP) in perforant path-granule cell synapses. Here we confirm this deficit in LTP and report that this strain of rat also displays impairments in long-term recognition memory when compared with normotensive controls. Further analysis of neurotrophin expression in dentate gyrus confirmed the previously-reported deficit in NGF and revealed a decrease in expression of brain-derived neurotrophic factor (BDNF), but not neurotrophin 3 (NT3) or neurotrophin 4 (NT4), in GH rats. These alterations in ligand expression were accompanied by changes in Trk receptor expression; specifically, a decrease in expression of TrkA and TrkB, but not TrkC, in the dentate gyrus of GH, compared with normotensive, rats. We conclude that the impairments in LTP and learning and memory observed in the GH strain are associated with aberrant expression of specific neurotrophic factors and their receptors in the dentate gyrus, adding weight to the evidence indicating a role for these proteins in several forms of synaptic plasticity.