Rong-Rong Mao

Antistress Effect of TRPV1 Channel on Synaptic Plasticity and Spatial Memory

BACKGROUND Stress is believed to exacerbate neuropsychiatric and cognitive disorders. In particular, the hippocampus, which plays critical roles in certain types of memory, including spatial memory, is exquisitely sensitive to stress. Certain types of memory are believed to depend on activity-dependent hippocampal synaptic plasticity such as long-term potentiation (LTP) and long-term depression (LTD), but stress suppresses LTP and facilitates LTD in the hippocampus and impairs spatial memory. Although the transient receptor potential vanilloid 1 (TRPV1 or VR1) is widely expressed in the hippocampus, it remains unknown whether the TRPV1 channel antagonizes the stress effects on hippocampal function. METHODS Using the TRPV1 agonists capsaicin and resiniferatoxin and selective antagonists capsazepine and SB366791, we examined the effect of TRPV1 activation on LTP and LTD in hippocampal CA1 slices of juvenile rats. Furthermore, we examined whether the effects of acute stress on synaptic plasticity and spatial memory could be prevented by intrahippocampal or intragastric infusion of a TRPV1 agonist. RESULTS The TRPV1 agonists capsaicin and resiniferatoxin facilitated LTP but suppressed LTD. Alterations were mediated by TRPV1 because the TRPV1 selective antagonists capsazepine and SB366791 blocked the actions of capsaicin. Acute stress suppressed LTP and enabled LTD, but the TRPV1 agonist capsaicin effectively prevented this effect. When capsaicin was intrahippocampally or intragastrically infused, the acute stress effect on impairing spatial memory retrieval was completely prevented. CONCLUSIONS The TRPV1 channel is a potential target to facilitate LTP and suppress LTD, in turn protecting hippocampal synaptic plasticity and spatial memory retrieval from the influence of acute stress.

Enriched environment experience overcomes the memory deficits and depressive-like behavior induced by early life stress

Stress in early life is believed to cause cognitive and affective disorders, and to disrupt hippocampal synaptic plasticity in adolescence into adult, but it is unclear whether exposure to enriched environment (EE) can overcome these effects. Here, we reported that housing rats in cages with limited nesting/bedding materials on postnatal days 2-21 reduced body weight gain, and this type of early life stress impaired spatial learning and memory of the Morris water maze and increased depressive-like behavior of the forced swim test in young adult rats (postnatal days 53-57). Early life stress also impaired long-term potentiation in hippocampal CA1 area of slices of young adult rats. Remarkably, EE experience on postnatal days 22-52 had no effect on spatial learning/memory and depressive-like behavior, but it significantly facilitated LTP in control rats, and completely overcame the effects of early life stress on young adult rats. These findings suggest that EE experience may be useful for clinical intervention in preventing cognitive and affective disorders during development.

Deep-brain magnetic stimulation promotes adult hippocampal neurogenesis and alleviates stress-related behaviors in mouse models for neuropsychiatric disorders

BackgroundRepetitive Transcranial Magnetic Stimulation (rTMS)/ Deep-brain Magnetic Stimulation (DMS) is an effective therapy for various neuropsychiatric disorders including major depression disorder. The molecular and cellular mechanisms underlying the impacts of rTMS/DMS on the brain are not yet fully understood.ResultsHere we studied the effects of deep-brain magnetic stimulation to brain on the molecular and cellular level. We examined the adult hippocampal neurogenesis and hippocampal synaptic plasticity of rodent under stress conditions with deep-brain magnetic stimulation treatment. We found that DMS promotes adult hippocampal neurogenesis significantly and facilitates the development of adult new-born neurons. Remarkably, DMS exerts anti-depression effects in the learned helplessness mouse model and rescues hippocampal long-term plasticity impaired by restraint stress in rats. Moreover, DMS alleviates the stress response in a mouse model for Rett syndrome and prolongs the life span of these animals dramatically.ConclusionsDeep-brain magnetic stimulation greatly facilitates adult hippocampal neurogenesis and maturation, also alleviates depression and stress-related responses in animal models.

Maternal separation exaggerates spontaneous recovery of extinguished contextual fear in adult female rats.

Early life stress increases the risk of posttraumatic stress disorders (PTSD). Patients with PTSD show impaired extinction of traumatic memory, and in women, this occurs more often when PTSD is preceded by child trauma. However, it is still unclear how early life stress accounts for extinction impairment. Here, we studied the effects of maternal separation (MS, postnatal day 2 to 14) on contextual fear extinction in adult female rats. Additionally, to examine changes in synaptic function affected by MS, we measured long-term potentiation (LTP) in prefrontal cortex and hippocampus in vitro, both of which have been implicated in fear extinction. We found that adult female rats had been subjected to MS exhibited significant spontaneous recovery of fear to the extinguished context. Furthermore, MS exposure resulted in LTP impairment in both infralimbic prefrontal cortex layer 2/3-layer 5 and hippocampal SC-CA1 pathways. Interestingly, no obvious effects of MS on contextual fear conditioning, fear recall as well as extinction training and recall were observed. Innate fear in the elevated plus maze or open field test remained nearly unaffected. These findings provided the first evidence that MS may exaggerate spontaneous recovery after contextual fear extinction, for which LTP impairment in the medial prefrontal cortex and hippocampus may be responsible, thereby possibly leading to impaired extinction associated with PTSD.

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.

Acute low-dose melamine affects hippocampal synaptic plasticity and behavior in rats.

Foods contaminated with melamine potentially cause risk to human health. However, the neurotoxicity of melamine has not been adequately assessed. Here, we aimed to examine the effects of acute low-dose exposure to melamine on hippocampal synaptic plasticity and behaviors in rats. We found that bath application of 50-500μg/ml melamine decreased basal synaptic transmission in the Schaffer collateral-CA1 pathway of hippocampal slices from postnatal days (P) 10-14 rats in a concentration-dependent manner; furthermore, this decrease in transmission was related to the reduction of presynaptic function as indicated by the increased paired-pulse facilitation ratio. Rats at 2-3months old were less vulnerable to the effects of 500μg/ml melamine on basal synaptic transmission when compared with P10-14 and P21-28 rats. Melamine (50μg/ml) significantly impaired long-term potentiation (LTP), without affecting long-term depression (LTD), in both P10-14 and 2-3month-old rats. Oral treatment with melamine (5 and 25mg/kg) 1h before behavioral tests significantly decreased the immobility time of the forced swim test in 2-3month-old rats and had no effect on locomotor activity in the open field test in both P21-28 and 2-3month-old rats. Our findings reveal some of the aspects of neurotoxicity induced by acute low-dose of melamine in hippocampal synaptic plasticity and behavior.

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.

Abnormal anxiety- and depression-like behaviors in mice lacking both central serotonergic neurons and pancreatic islet cells

Dysfunction of central serotonin (5-HT) system has been proposed to be one of the underlying mechanisms for anxiety and depression, and the association of diabetes mellitus and psychiatric disorders has been noticed by the high prevalence of anxiety/depression in patients with diabetes mellitus. This promoted us to examine these behaviors in central 5-HT-deficient mice and those also suffering with diabetes mellitus. Mice lacking either 5-HT or central serotonergic neurons were generated by conditional deletion of Tph2 or Lmx1b respectively. Simultaneous depletion of both central serotonergic neurons and pancreatic islet cells was achieved by administration of diphtheria toxin (DT) in Pet1-Cre;Rosa26-DT receptor (DTR) mice. The central 5-HT-deficient mice showed reduced anxiety-like behaviors as they spent more time in and entered more often into the light box in the light/dark box test compared with controls; similar results were observed in the elevated plus maze test. However, they displayed no differences in the immobility time of the forced swimming and tail suspension tests suggesting normal depression-like behaviors in central 5-HT-deficient mice. As expected, DT-treated Pet1-Cre;Rosa26-DTR mice lacking both central serotonergic neurons and pancreatic islet endocrine cells exhibited several classic diabetic symptoms. Interestingly, they displayed increased anxiety-like behaviors but reduced immobility time in the forced swimming and tail suspension tests. Furthermore, the hippocampal neurogenesis was dramatically enhanced in these mice. These results suggest that the deficiency of central 5-HT may not be sufficient to induce anxiety/depression-like behaviors in mice, and the enhanced hippocampal neurogenesis may contribute to the altered depression-like behaviors in the 5-HT-deficient mice with diabetes. Our current investigation provides understanding the relationship between diabetes mellitus and psychiatric disorders.