Qi-Xin Zhou

Chronic Morphine Treatment Impaired Hippocampal Long-Term Potentiation and Spatial Memory via Accumulation of Extracellular Adenosine Acting on Adenosine A1 Receptors

Chronic exposure to opiates impairs hippocampal long-term potentiation (LTP) and spatial memory, but the underlying mechanisms remain to be elucidated. Given the well known effects of adenosine, an important neuromodulator, on hippocampal neuronal excitability and synaptic plasticity, we investigated the potential effect of changes in adenosine concentrations on chronic morphine treatment-induced impairment of hippocampal CA1 LTP and spatial memory. We found that chronic treatment in mice with either increasing doses (20–100 mg/kg) of morphine for 7 d or equal daily dose (20 mg/kg) of morphine for 12 d led to a significant increase of hippocampal extracellular adenosine concentrations. Importantly, we found that accumulated adenosine contributed to the inhibition of the hippocampal CA1 LTP and impairment of spatial memory retrieval measured in the Morris water maze. Adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine significantly reversed chronic morphine-induced impairment of hippocampal CA1 LTP and spatial memory. Likewise, adenosine deaminase, which converts adenosine into the inactive metabolite inosine, restored impaired hippocampal CA1 LTP. We further found that adenosine accumulation was attributable to the alteration of adenosine uptake but not adenosine metabolisms. Bidirectional nucleoside transporters (ENT2) appeared to play a key role in the reduction of adenosine uptake. Changes in PKC-α/β activity were correlated with the attenuation of the ENT2 function in the short-term (2 h) but not in the long-term (7 d) period after the termination of morphine treatment. This study reveals a potential mechanism by which chronic exposure to morphine leads to impairment of both hippocampal LTP and spatial memory.

Actin Polymerization-Dependent Increase in Synaptic Arc/Arg3.1 Expression in the Amygdala Is Crucial for the Expression of Aversive Memory Associated with Drug Withdrawal

Aversive memories associated with drug withdrawal may contribute to persistent drug seeking. Molecular mechanisms that are critical for aversive memory formation have yet to be elucidated. Recently, we showed in a rat conditioned place aversion (CPA) model that synaptic actin polymerization in the amygdala were required for aversive memory information. Here, we demonstrated that actin polymerization within the amygdala triggered transportation of activity-regulated cytoskeletal-associated protein (Arc/Arg3.1) into amygdalar synapses. Increased synaptic Arc/Arg3.1 expression contributed to aversive memory formation by regulating synaptic AMPA receptor (AMPAR) endocytosis, as in vivo knockdown of amygdalar Arc/Arg3.1 with Arc/Arg3.1-shRNA prevented both AMPAR endocytosis and CPA formation. We also demonstrated that conditioned morphine withdrawal led to induction of LTD in the amygdala through AMPAR endocytosis. We further demonstrated that Arc/Arg3.1-regulated AMPAR endocytosis was GluR2 dependent, as intra-amygdala injection of Tat-GluR23Y, a GluR2-derived peptide that has been shown to specifically block regulated, but not constitutive, AMPAR endocytosis, prevented AMPAR endocytosis, LTD induction, and aversive memory formation. Therefore, this study extends previous studies on the role of actin polymerization in synaptic plasticity and memory formation by revealing the critical molecular events involved in aversive memory formation as well as LTD induction, and by showing that Arc/Arg3.1 is a crucial mediator for actin polymerization functions, and, thus, underscores the unknown details of how actin polymerization mediates synaptic plasticity and memory.

Chronic Clomipramine Treatment Reverses Core Symptom of Depression in Subordinate Tree Shrews

Chronic stress is the major cause of clinical depression. The behavioral signs of depression, including anhedonia, learning and memory deficits, and sleep disruption, result from the damaging effects of stress hormones on specific neural pathways. The Chinese tree shrew (Tupaia belangeri chinensis) is an aggressive non-human primate with a hierarchical social structure that has become a well-established model of the behavioral, endocrine, and neurobiological changes associated with stress-induced depression. The tricyclic antidepressant clomipramine treats many of the core symptoms of depression in humans. To further test the validity of the tree shrew model of depression, we examined the effects of clomipramine on depression-like behaviors and physiological stress responses induced by social defeat in subordinate tree shrews. Social defeat led to weight loss, anhedonia (as measured by sucrose preference), unstable fluctuations in locomotor activity, sustained urinary cortisol elevation, irregular cortisol rhythms, and deficient hippocampal long-term potentiation (LTP). Clomipramine ameliorated anhedonia and irregular locomotor activity, and partially rescued the irregular cortisol rhythm. In contrast, weight loss increased, cortisol levels were even higher, and in vitro LTP was still impaired in the clomipramine treatment group. These results demonstrate the unique advantage of the tree shrew social defeat model of depression.

White-matter volume reduction and the protective effect of immunosuppressive therapy in systemic lupus erythematosus patients with normal appearance by conventional magnetic resonance imaging.

Objective. The central nervous system (CNS) is often affected by systemic lupus erythematosus (SLE), but assessment of CNS outcomes using noninvasive cerebral structural measures remains in its infancy. Magnetic resonance imaging (MRI) with expert visual interpretation is critical to diagnosis, but does not permit quantitative measurements. Our pilot study investigated whether quantitative brain volumetric analyses could be used to detect white-matter (WM) abnormalities and responses to treatment in SLE (ClinicalTrials.gov: NCT00703742). Methods. Forty-two pairs of SLE patients and healthy controls underwent high-resolution 3-dimensional structural MRI scans. Combining voxel-based morphometry and region of interest analyses, subtle WM volume abnormalities in whole brains from SLE patients were identified, and regional WM volume was calculated. Associations between WM volume and symptom severity, as well as the effects of immunosuppressive therapy, were then investigated. Results. The WM volume of the SLE group was significantly decreased in the bilateral posterior and anterior crus of the internal capsule (PIC and AIC, respectively), the subgyral right frontal lobe, and left temporal lobe (p < 0.001). Regional WM volume (left PIC and right AIC) was correlated with SLEDAI scores. The WM volume of patients treated with immunosuppressive therapy was greater than that of patients who were never treated with immunosuppressive therapy. Conclusion. Quantitative brain volumetric analyses detect brain injuries in WM for SLE that are not obvious by conventional MRI, and may be adequately sensitive and quantitative to measure the effect of therapeutic interventions in preventing brain injury and outcomes in SLE.

The bidirectional effects of hypothyroidism and hyperthyroidism on anxiety- and depression-like behaviors in rats

Thyroid hormone disorders have long been linked to depression, but the causal relationship between them remains controversial. To address this question, we established rat models of hypothyroidism using (131)iodine ((131)I) and hyperthyroidism using levothyroxine (LT4). Serum free thyroxine (FT4) and triiodothyronine (FT3) significantly decreased in the hypothyroid of rats with single injections of (131)I (5mCi/kg). These rats exhibited decreased depression-like behaviors in forced swimming test and sucrose preference tests, as well as decreased anxiety-like behaviors in an elevated plus maze. Diminished levels of brain serotonin (5-HT) and increased levels of hippocampal brain-derived neurotrophic factor (BDNF) were found in the hypothyroid rats compared to the control saline-vehicle administered rats. LT4 treatment reversed the decrease in thyroid hormones and depression-like behaviors. In contrast, hyperthyroidism induced by weekly injections of LT4 (15μg/kg) caused a greater than 10-fold increase in serum FT4 and FT3 levels. The hyperthyroid rats exhibited higher anxiety- and depression-like behaviors, higher brain 5-HT level, and lower hippocampal BDNF levels than the controls. Treatment with the antidepressant imipramine (15mg/kg) diminished serum FT4 levels as well as anxiety- and depression-like behaviors in the hyperthyroid rats but led to a further increase in brain 5-HT levels, compared with the controls or the hypothyroid rats. Together, our results suggest that hypothyroidism and hyperthyroidism have bidirectional effects on anxiety- and depression-like behaviors in rats, possibly by modulating hippocampal BDNF levels.

Inhibition of Rac1 Activity in the Hippocampus Impairs the Forgetting of Contextual Fear Memory

Fear is crucial for survival, whereas hypermnesia of fear can be detrimental. Inhibition of the Rac GTPase is recently reported to impair the forgetting of initially acquired memory in Drosophila. Here, we investigated whether inhibition of Rac1 activity in rat hippocampus could contribute to the hypermnesia of contextual fear. We found that spaced but not massed training of contextual fear conditioning caused inhibition of Rac1 activity in the hippocampus and heightened contextual fear. Furthermore, intrahippocampal injection of the Rac1 inhibitor NSC23766 heightened contextual fear in massed training, while Rac1 activator CN04-A weakened contextual fear in spaced training rats. Our study firstly demonstrates that contextual fear memory in rats is actively regulated by Rac1 activity in the hippocampus, which suggests that the forgetting impairment of traumatic events in posttraumatic stress disorder may be contributed to the pathological inhibition of Rac1 activity in the hippocampus.

Impaired contextual fear extinction and hippocampal synaptic plasticity in adult rats induced by prenatal morphine exposure

Prenatal opiate exposure causes a series of neurobehavioral disturbances by affecting brain development. However, the question of whether prenatal opiate exposure increases vulnerability to memory‐related neuropsychiatric disorders in adult offspring remains largely unknown. Here, we found that rats prenatally exposed to morphine (PM) showed impaired acquisition but enhanced maintenance of contextual fear memory compared with control animals that were prenatally exposed to saline (PS). The impairment of acquisition was rescued by increasing the intensity of footshocks (1.2 mA rather than 0.8 mA). Meanwhile, we also found that PM rats exhibited impaired extinction of contextual fear, which is associated with enhanced maintenance of fear memory. The impaired extinction lasted for 1 week following extinction training. Furthermore, PM rats exhibited reduced anxiety‐like behavior in the elevated plus‐maze and light/dark box test without differences in locomotor activity. These alterations in PM rats were mirrored by abnormalities in synaptic plasticity in the Schaffer collateral‐CA1 synapses of the hippocampus in vivo. PS rats showed blocked long‐term potentiation and enabled long‐term depression in CA1 synapses following contextual fear conditioning, while prenatal morphine exposure restricted synaptic plasticity in CA1 synapses. The smaller long‐term potentiation in PM rats was not further blocked by contextual fear conditioning, and the long‐term depression enabled by contextual fear conditioning was abolished. Taken together, our results provide the first evidence suggesting that prenatal morphine exposure may increase vulnerability to fear memory‐related neuropsychiatric disorders in adulthood.

Effects of pentylenetetrazol-induced brief convulsive seizures on spatial memory and fear memory

Previous studies have demonstrated that in the pentylenetetrazol (PTZ) kindling model, recurrent seizures either impair or have no effect on learning and memory. However, the effects of brief seizures on learning and memory remain unknown. Here, we found that a single injection of a convulsive dose of PTZ (50 mg/kg, ip) induced brief seizures in Sprague-Dawley rats. Administration of PTZ before training impaired the acquisition of spatial memory in the Morris water maze (MWM) and fear memory in contextual fear conditioning. However, the administration of PTZ immediately after training did not affect memory consolidation in either task. These findings suggest that brief seizures have different effects on acquisition and consolidation of spatial and fear memory.

A depression model of social defeat etiology using tree shrews

Depression is a common neuropsychiatric disorder, marked by depressed mood for at least two weeks. The World Health Organization predicts that depression will be the number one leading cause of disease and injury burden by 2030. Clinical treatment faces at least three serious obstacles. First, the disease mechanism is not fully understood and thus there are no effective ways to predict and prevent depression and no biological method of diagnosis. Second, available antidepressants are based on monoamine mechanisms that commonly have a long delay of action and possibly cause a higher risk of suicide. Third, no other antidepressant mechanisms are available, with fast action and few side effects. Unfortunately, several decades of research based on rodent models of depression have not been successful in resolving these problems, at least partially due to the huge differences in brain function between rodents and people. Tree shrews are the closest sister to primates, and brain functions in these species are closer to those of humans. In this review, we discuss a tree shrew model of depression with social defeat etiology and aspects of construct, face and predicted validity of an animal model. Although a tree shrew model of depression has long been ignored and not fully established, its similarities to those aspects of depression in humans may open a new avenue to address this human condition.

Light exposure before learning improves memory consolidation at night

Light is recently recognized as a modulator able to activate the hippocampus and modulate memory processing, but little is known about the molecular mechanisms. Here, we report that in mice, a short pulse of white light before learning dramatically improves consolidation of contextual fear memory during the night. The light exposure increases hippocampal active p21-activated kinase 1 (PAK1) and CA1 long-term potentiation (LTP). These light effects are abolished in PAK1 knockout and dominant-negative transgenic mice, but preserved by expression of constitutively active PAK1 in the hippocampus. Our results indicate that light can act as a switch of PAK1 activity that modulate CA1 LTP and thereby memory consolidation without affecting learning and short-term memory.