Chronic stress and stressful emotional contagion affect the empathy-like behavior of rats.

Empathy is a potential motivation for prosocial behaviors that is related to many psychiatric diseases, such as major depressive disorder; however, its neural mechanisms remain unclear. To elucidate the relationship between empathy and stress, we established a chronic stress contagion (SC) procedure combined with chronic unpredictable mild stress (CUMS) to investigate (1) whether depressive rats show impaired empathy-like behavior toward fearful conspecifics, (2) whether frequent social contact with normal familiar conspecifics (social support) alleviates the negative effects of CUMS, and (3) the effect of long-term exposure to a depressed partner on emotional and empathic responses in normal rats. We found that the CUMS group showed less empathy-like behavior in the social transfer of fear model (STFM), as indicated by less social interaction with the demonstrator and reduced freezing behavior in the fear-expression test. Social contact partially alleviated depression-like behaviors and the negative effect of CUMS in the fear-transfer test. The normal rats who experienced stress contagion from daily exposure to a depressed partner for 3 weeks showed lower anxiety and increased social response in the fear-transfer test than the control group. We concluded that chronic stress impairs empathy-like behaviors, while social contact partially buffers the effect of CUMS. Thus, social contact or contagion of stress is mutually beneficial to both stressed individuals and nonstressed partners. Higher dopamine and lower norepinephrine levels in the basolateral amygdala probably contributed to these beneficial effects.

Phencynonate hydrochloride exerts antidepressant effects by regulating the dendritic spine density and altering glutamate receptor expression.

Phencynonate hydrochloride (PCH) is a drug that crosses the blood-brain barrier. Cellular experiments confirmed that PCH protects against glutamate toxicity and causes only weak central inhibition and limited side effects. As shown in our previous studies, PCH alleviates depression-like behaviours induced by chronic unpredictable mild stress (CUMS). Here we administered PCH at three different doses (4, 8 and 16 mg/kg) to male rats for two continuous days after CUMS and conducted behavioural tests to assess the dose-dependent antidepressant effects of PCH and its effects on the neuroplasticity in the hippocampus and medial prefrontal cortex (mPFC). Meanwhile, we measured the spine density and expression of related proteins to illustrate the mechanism of PCH. PCH treatment (8 mg/kg) significantly alleviated depression-like behaviours induced by CUMS. All doses of PCH treatment reversed the spine loss in prelimbic and CA3 regions induced by CUMS. Kalirin-7 expression was decreased in the hippocampus and mPFC of the CUMS group. The expression of the NR1 and NR2B subunits in the hippocampus, and NR2B in mPFC are increased by CUMS. PCH treatment (8 and 16 mg/kg) reversed all of these changes of Kalirin-7 in PFC and hippocampus, as well as NR1 and NR2B expression in the hippocampus. PCH is expected to be developed as a new type of rapid antidepressant. Its antidepressant effect may be closely related to the modulation of dendritic spine density in the prelimbic and CA3 regions and the regulation of Kalilin-7 and N-methyl-D-aspartic acid receptor levels in the hippocampus.

Involvement of D2 receptor in the NAc in chronic unpredictable stress-induced depression-like behaviors.

D2 receptors (D2Rs) located in both pre- and postsynaptic membranes of medium spiny neurons (MSNs) in the nucleus accumbens (NAc) are involved in the stress response and associated behaviors. The role of D2Rs in chronic unpredictable stress (CUS)-induced depression-like behaviors is not clear. Quinpirole (a D2R agonist) and eticlopride (a D2R antagonist) were stereotactically delivered into the NAc before Sprague Dawley rats underwent CUS. CUS-induced depression-like behaviors were accompanied by a significant decrease in both the dopamine (DA) level and D2R expression in the NAc. Eticlopride reversed CUS-induced depression-like behavior and rescued the DA levels in the NAc, and microinjection of DA into the NAc of CUS individuals had the same effect as eticlopride. By contrast, delivery of quinpirole into the NAc of control animals induced depression-like behaviors accompanied by a decrease in the DA level in the NAc. These results show that DA plays a key role in CUS-induced depression-like behaviors and the D2R exerts a presynaptic negative feedback on DA levels during CUS. Microinjection of quinpirole into the NAc also decreased the level of the kalirin-7 protein in the NAc of both control and stressed animals, while eticlopride increased its level in the NAc of rats. In agreement with these results, intraperitoneal injection of eticlopride in mice also caused an increase in both the kalirin-7 protein level in the NAc and spine density in MSNs, while quinpirole reduced them. These results suggest that regulation of kalirin-7 through D2R in the NAc is a general pathway in rats and mice, and is involved in CUS-induced depression-like behaviors. Kalirin-7 may be directly regulated through the D2R postsynaptic pathway or indirectly through the presynaptic pathway in the NAc. The interaction between D2R and kalirin-7 needs to be investigated further.

Dendritic Spines in Depression: What We Learned from Animal Models.

Depression, a severe psychiatric disorder, has been studied for decades, but the underlying mechanisms still remain largely unknown. Depression is closely associated with alterations in dendritic spine morphology and spine density. Therefore, understanding dendritic spines is vital for uncovering the mechanisms underlying depression. Several chronic stress models, including chronic restraint stress (CRS), chronic unpredictable mild stress (CUMS), and chronic social defeat stress (CSDS), have been used to recapitulate depression-like behaviors in rodents and study the underlying mechanisms. In comparison with CRS, CUMS overcomes the stress habituation and has been widely used to model depression-like behaviors. CSDS is one of the most frequently used models for depression, but it is limited to the study of male mice. Generally, chronic stress causes dendritic atrophy and spine loss in the neurons of the hippocampus and prefrontal cortex. Meanwhile, neurons of the amygdala and nucleus accumbens exhibit an increase in spine density. These alterations induced by chronic stress are often accompanied by depression-like behaviors. However, the underlying mechanisms are poorly understood. This review summarizes our current understanding of the chronic stress-induced remodeling of dendritic spines in the hippocampus, prefrontal cortex, orbitofrontal cortex, amygdala, and nucleus accumbens and also discusses the putative underlying mechanisms.

[The interaction between gamma-aminobutyric acid and other related neurotransmitters in depression].

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter of the central nervous system (CNS) in mammalian, which involved in several mood disorders such as anxiety, depression and schizophrenia. Nowadays, there are growing evidences showed that the depression is concerned with a deficiency in brain GABA. However, there are numerous studies based on the monoamine hypothesis and glutamatergic dysfunction, while the study on GABA is relatively less and scattered. Our aim is to discuss the relationship between depression and GABA by introducing the role of GABA receptors and the interaction between GABA and 5-hydroxytryptamine, dopamine and glutamic acid. It provides new ideas for further study on the pathogenesis and therapy of depression.

[Hippocampus quinolinic acid modulates glutamate and NMDAR/mGluR1 in chronic unpredictable mild stress-induced depression].

The present study was to investigate the role of the quinolinic acid (QUIN) and its relationship with N-methyl-D-aspartic acid (NMDA) receptor and metabotropic glutamate receptor 1 (mGluR1) in depression induced by chronic unpredictable mild stress (CUMS) in hippocampus. CUMS-induced depression model was established in Sprague-Dawley rats. Intrahippocampal injections of QUIN, QUIN antagonist Ro61-8048, non-competitive NMDA receptor antagonist MK-801 and mGluR1 antagonist AIDA were respectively adopted by rat brain stereotaxic coordinates. The behavioral observations were conducted by measurement of weight changes, sucrose preference test, open-field test and tail suspension test. The concentration of glutamic acid (Glu) and the expression of its receptor subunits in hippocampus were detected by HPLC and Western blot, respectively. The QUIN content in hippocampus was determined by enzyme linked immunosorbent assay (ELISA). The result showed that CUMS significantly induced the depressive-like behaviors in rats, increased the contents of QUIN and Glu, and upregulated the expression of NMDA receptor subunits NR2B and mGluR1 in hippocampus. Microinjection of QUIN into hippocampus resulted in animal depressive-like behaviors, and increased the content of Glu and the expression of NR2B and mGluR1 significantly. QUIN antagonist Ro61-8048 effectively restrained the depression-like behaviors induced by CUMS, and decreased the content of Glu and the expression of NR2B and mGluR1 significantly. Intrahippocampal injections of MK-801 and AIDA effectively improved the depression-like behaviors induced by CUMS and decreased the Glu content. The results suggest that CUMS may contribute to the production and release of QUIN in hippocampal microglia. QUIN results in elevation of Glu level via NMDA receptor and mGluR1, and the increase of expression of NR2B and mGluR1 in hippocampus, which leads to depression-like behaviors in the end.

[Modulation of hippocampal glutamate and NMDA/AMPA receptor by homocysteine in chronic unpredictable mild stress-induced rat depression].

The study was to investigate the role of homocysteine (Hcy) which was released by hippocampal glial cells and its relationship with NMDA receptor and AMPA receptor in depression induced by chronic unpredictable mild stress (CUMS), and explore the mechanism of changes of Glu/Glu receptor in glial cells and neurons. CUMS-induced depression model was established. The body weight of rats was weighed on the 1st, 7th, 14th, and 21st days during the experiment. The behavioral performances were observed by means of sucrose consumption test, open field test and tail suspension test. Intrahippocampal microinjection of Hcy, NMDA receptor antagonist MK-801 and AMPA receptor antagonist NBQX was performed under stereotaxic guide cannula. The concentration of Glu and the expression of its receptors' subunits were detected respectively by high performance liquid chromatography (HPLC) and Western blot. The Hcy content and the levels of phosphorylation of NMDA receptor and AMPA receptor in hippocampus were separately determined by enzyme linked immunosorbent assay (ELISA). The results showed that CUMS significantly induced the depression-like behaviors in rats, and the content of Glu and Hcy, the expression of NMDA receptors' subunits NR1/NR2B and the level of phosphorylation of NMDA receptor (p-NMDAR) in hippocampus increased significantly, while the expression of AMPA receptors' subunits GluR2/3 and the level of phosphorylation of AMPA receptor (p-AMPAR) decreased significantly. Microinjection of Hcy into hippocampus resulted in similar animal depression-like behaviors and increased Glu content compared to the CON/SAL group, the expression of NR1/NR2B/GluR2/3 and the level of p-NMDAR increased significantly, but the level of p-AMPAR reduced observably. Intrahippocampal injections of MK-801 effectively improved the depression-like behaviors induced by CUMS and Hcy, and attenuated the elevation of Glu content induced by Hcy in hippocampus, whereas NBQX could not improve the depression-like behaviors, but also decreased the Glu content induced by Hcy remarkably. These results suggest that CUMS may contribute to the production and release of Hcy via hippocampal astrocytes. Through the increase of expression of NR1/NR2B/GluR2/3 and level of p-NMDAR, and the decrease of level of p-AMPAR, Hcy results in elevation of Glu level, which leads to depression-like behaviors in the end. In a word, the Hcy released by astrocytes plays an important role in stress-induced elevation of Glu content and variation of NMDA/AMPA receptors in hippocampus.

The effects of neonatal paternal deprivation on pair bonding, NAcc dopamine receptor mRNA expression and serum corticosterone in mandarin voles.

High levels of paternal care are important for the development of social behavior in monogamous rodents. However, the effects of paternal care on the formation of pair bonding and underlying neuroendocrine mechanisms, especially the involvements of dopamine system and corticosterone, are not well understood. We investigated effects of paternal deprivation on pair bonding in mandarin voles (Microtus mandarinus), a socially monogamous rodent. Paternal deprivation was found to inhibit the formation of pair bonding in females according to partner preference tests (PPT). Paternal deprivation also reduced body contact behavior and increased aggression in males and females in PPT. During social interaction tests (SIT), paternal deprivation was found to reduce investigative and aggressive behaviors but increase body contact and self-grooming in females, and reduce staring, aggression, body contact and self-grooming in males when interacting with the opposite sex. Paternal deprivation reduced the expression of dopamine 1-type receptor (D1R) mRNA and dopamine 2-type receptor (D2R) mRNA in the nucleus accumbens of female offspring in later life, but enhanced mRNA expression of these two dopamine receptors in males. After three days of cohabitation the expression of D1R mRNA and D2R mRNA was negatively correlated for voles reared by two parents, but positively correlated in paternally deprived animals. Paternal deprivation reduced serum corticosterone levels in females but had the opposite effect in males. Three days of cohabitation did not alter corticosterone levels of PD females, but reduced it in PC females. Our results provide substantial evidence that paternal deprivation inhibits the formation of pair bonding in female mandarin voles and alters social behavior later in life. These behavioral variations were possibly associated with sex-specific alterations in the expression of two types of dopamine receptors and serum corticosterone levels induced by paternal deprivation.

Endogenous hippocampal estrogen is involved in stress-induced depression-like behaviors and spine plasticity in male rats.

The estrogen (17ß-estradiol, E2) level in the hippocampus is higher and more stable in male rats than female rats. Both stress and estrogen affect spine plasticity, and many studies have demonstrated that peripheral estrogen treatment can prevent stress-induced spine loss in both males and females. Some in vitro studies have indicated that neural estrogen (nE2) participates in the modulation of spine plasticity in cultured neurons. However, whether nE2 regulates spine density in vivo in males is not clear, and the specific role of nE2 in stress-induced depression-like behaviors of male rats remains unknown. We delivered letrozole (a selective aromatase inhibitor that blocks the conversion of testosterone to estradiol) and estrogen into the hippocampus of rats and found that letrozole treatment induced the same depression-like behaviors in control rats as observed in chronic unpredictable mild stress (CUMS) rats. Estrogen treatment reversed/or alleviated depression-like behaviors induced by CUMS or letrozole infusion and elevated Kalirin-7 expression in hippocampus. Estrogen treatment also rescued letrozole-induced spine loss. Expression of GluN1 and PSD-95 also changed with Kalirin-7 and spine density. All these proteins were decreased in CUMS rats and letrozole infusion rats but increased in rats treated with estrogen. In conclusion, nE2 in the hippocampus plays an important role in CUMS-induced depression-like behaviors in male rats and Kalirin-7 is involved in this process. GluN1 and PSD-95 possibly mediate the regulation of Kalirin-7 by nE2, which ultimately leads to changes in spine density and depression-like behaviors.

[Activation of hippocampal D1 dopamine receptor inhibits glutamate-mediated depression induced by chronic unpredictable mild stress in rats].

The present study was to investigate the role of dopamine D1 receptors and its relationship with glutamate, N-methyl-D-aspartic acid (NMDA) receptor and α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor in depression induced by chronic unpredictable mild stress (CUMS). CUMS-induced depression model was established in Sprague-Dawley rats, and intrahippocampal microinjections of D1 dopamine receptor agonist SKF38393, non-competitive NMDA receptor antagonist MK-801 and AMPA receptor antagonist NBQX were respectively adopted by rat brain stereotaxic coordinates. The behavioral observations were conducted by measurement of weight changes, sucrose preference test, open-field test and tail suspension test. The concentration of glutamic acid and the expression of its receptors' subunits were detected by HPLC and Western blot, respectively. The results showed that, compared with control group, CUMS rats showed depression-like behavioral changes, higher concentration of glutamic acid, lower expressions of NMDA receptor (NR1) and AMPA receptor (GluR2/3) in hippocampus. Pretreatment with injection of SKF38393 could rescue such depression effect of CUMS, decrease the concentration of glutamic acid, and increase the expressions of NMDA receptor (NR1), AMPA receptor (GluR2/3) in hippocampus. Pretreatment with MK-801 could enhance the antidepressant effect of SKF38393, while NBQX weakened. These results suggest that agonists of D1 dopamine receptor could reduce the concentration of glutamic acid in hippocampus, and its antidepressant effect may be mediated by AMPA receptor partially.

[Research progress of BDNF and depression].

BDNF is widespread existed in CNS and PNS, because of its function in nerve regeneration and restoration, more and more researches focused on the effect of BDNF on neural plasticity in the development of depression and the mechanisms of antidepressant. This article review the basic results and the research trends on BDNF and depression at present, more researches about the interactions of BDNF and proBDNF, BDNF and other transmitters and their receptors should be expected.

Endogenous hippocampal, not peripheral, estradiol is the key factor affecting the novel object recognition abilities of female rats.

Estradiol (E2) is involved in the regulation of emotional behavior, cognitive function, and neuroplasticity. However, peripheral E2 and central E2 levels do not always fluctuate together. The relationships of peripheral and central E2 with cognitive function are not clear. The aim of this study was to investigate whether peripheral E2, hippocampal E2, or both play a critical role in novel object recognition (NOR), and whether Kalirin-7, an important regulator of spine plasticity, is involved in the modulation of E2 on cognitive behavior. Our results showed that ovariectomy (OVX) significantly reduced serum E2 levels in the 14 weeks following the procedure. However, hippocampal E2 levels did not decrease in the OVX group compared to the sham group until after 14 weeks. Consistent with the changes in hippocampal E2 levels, the investigation ratio in the NOR test and hippocampal Kalirin-7 expression was also not lower in the OVX group than in the sham group until 14 weeks after the procedure. To confirm the relationship between hippocampal E2 levels and NOR ability, we inhibited the production of hippocampal E2 via microinjection of letrozole (LTZ; an aromatase inhibitor) into the hippocampi of rats in the control group and 8-week OVX group. The data indicated that a reduction in E2 levels in the hippocampus significantly impaired NOR ability and simultaneously decreased Kalirin-7 levels in the hippocampus. In conclusion, our study strongly demonstrates that hippocampal E2, but not peripheral E2, plays a critical role in NOR ability and that Kalirin-7 may be involved in this mechanism. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Different baseline physical activity predicts susceptibility and resilience to chronic social defeat stress in mice: Involvement of dopamine neurons.

Physical inactivity, the fourth leading mortality risk factor worldwide, is associated with chronic mental illness. Identifying the mechanisms underlying different levels of baseline physical activity and the effects of these levels on the susceptibility to stress is very important. However, whether different levels of baseline physical activity influence the susceptibility and resilience to chronic social defeat stress (CSDS), and the underlying mechanisms in the brain remain unclear. The present study segregated wild-type mice into low baseline physical activity (LBPA) and high baseline physical activity (HBPA) groups based on short term voluntary wheel running (VWR). LBPA mice showed obvious susceptibility to CSDS, while HBPA mice were resilient to CSDS. In addition, the expression of tyrosine hydroxylase (TH) in the ventral tegmental area (VTA) was lower in LBPA mice than in HBPA mice. Furthermore, activation of TH neurons in the VTA of LBPA mice by chemogenetic methods increased the levels of VWR and resilience to CSDS. In contrast, inhibiting TH neurons in the VTA of HBPA mice lowered the levels of VWR and increased their susceptibility to CSDS. Thus, this study suggests that different baseline physical activities might be mediated by the dopamine system. This system also affects the susceptibility and resilience to CSDS, possibly via alteration of the baseline physical activity. This perspective on the neural control and impacts on VWR may aid the development of strategies to motivate and sustain voluntary physical activity. Furthermore, this can maximize the impacts of regular physical activity toward stress-reduction and health promotion.

[Antidepressant effect of microinjection of neuropeptide Y into the hippocampus is mediated by decreased expression of nitric oxide synthase].

Accumulating evidence indicates an important role of hippocampal dendrite atrophy in the development of depression, while neuropeptide Y (NPY) participates in hippocampal dendrite growth. The present study was aimed to investigate the relationship between NPY and nitric oxide synthase (NOS) in chronic unpredictable mild stress (CUMS)-induced depression. CUMS-induced depression model was established in Sprague-Dawley rats. Intrahippocampal microinjections of NPY, NPY-Y1 receptor antagonist GR231118 and non-specific NOS inhibitor N-nitro-L-arginine methyl ester (L-NAME) were respectively adopted by rat brain stereotaxic coordinates. The behavioral observations were conducted by sucrose consumption test, open field test and forced swimming test. The expressions of NPY, neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS) in hippocampus were detected by immunohistochemistry. The results showed that, compared with the control group, rats receiving CUMS for 21 d or intrahippocampal microinjection of GR231118 showed a significant reduction in body weight and depression-like behavior, which included reductions in sucrose preference, locomotor activity, rearing and grooming in open field test, and increased duration of immobility in forced swimming test. Moreover, the expression of NPY significantly decreased (P<0.01), while the expressions of nNOS and iNOS increased obviously in the hippocampal dentate gyrus (DG) and CA3 regions (P<0.01). Intrahippocampal microinjections of NPY prevented the depression-like behavioral changes induced by CUMS and decreased the expressions of nNOS and iNOS in the hippocampal DG and CA3 regions (P<0.01). Intrahippocampal microinjections of GR231118 reduced behavioral ability of the rats dramatically and significantly increased the expressions of hippocampal nNOS and iNOS (P<0.01). Intrahippocampal microinjections of L-NAME suppressed the depression-like behavioral changes induced by CUMS or intrahippocampal microinjection of GR231118. In conclusion, reduced expression of NPY and increased expression of NOS in hippocampus may make significant contributions to CUMS-induced depression. These results suggest that the antidepressant function of NPY associates with down-regulation of NOS expression in hippocampus, possibly mediated via NPY-Y1 receptor.

[Involvement of hippocampal NMDA receptor and neuropeptide Y in depression induced by chronic unpredictable mild stress].

The present study was aimed to investigate the role and relationship between N-methyl-D-aspartic acid (NMDA) receptor and neuropeptide Y (NPY) in depression induced by chronic unpredictable mild stress (CUMS). CUMS-induced depression model was established in Sprague-Dawley rats. Intrahippocampal injections of NMDA, non-competitive NMDA receptor antagonist MK-801 and NPY-Y1 receptor antagonist GR231118 were respectively adopted by rat brain stereotaxic coordinates. The behavioral observations were conducted by sucrose consumption test, open field test and forced swimming test. The expression of NPY in hippocampus was detected by immunohistochemistry. The results showed that compared with the control group, rats receiving CUMS for 21 days or intrahippocampal injection of GR231118 or NMDA showed depression-like behavioral changes, including a reduction in sucrose preference, body weight, locomotor activity, rearing and grooming in open field test, and increased duration of immobility in forced swimming test. Intrahippocampal injection of NMDA decreased the expression of NPY in hippocampal CA3 region and dentate gyrus (DG) region. Intrahippocampal injection of MK-801 improved the depression-like behavioral changes induced by CUMS, and increased the expression of NPY in hippocampal CA3 region and DG region. Co-injection of GR231118 and MK-801showed that GR231118 suppressed the antidepressant effect of MK-801. These data suggest that CUMS might induce depression through excessive release of glutamate (Glu), over-activation of NMDA receptors, and downregulation of NPY. Antidepressant effect of NPY was mainly mediated via NPY-Y1 receptor.

Alteration in oxytocin levels induced by early social environment affects maternal behavior and estrogen receptor alpha in mandarin voles (Microtus mandarinus).

Many studies have shown that the early social environment exerts long-term effects on the brain and also the parental behavior of adults. Oxytocin (OXT) is one of the most important neurotransmitters that regulate social behavior; howerve, whether the early social environment affects parental behavior via OXT remains unclear. Using socially monogamous adult mandarin voles (Microtus mandarinus), the present study found that 1) both paternal deprivation and early social deprivation significantly decreased OXT expression in both the paraventricular hypothalamic nucleus (PVN) and the supraoptic nucleus (SON) of F2 generation offspring; 2) systemic neonatal OXT injection in naïve animals promoted maternal but not paternal behavior in adult F2 offspring; 3) systemic neonatal OXT injection significantly increased ERα expression in both the medial preoptic area (MPOA) and the ventro medial hypothalamic nucleus (VMH) in female but not in male mandarin voles; 4) systemic neonatal administration of an OXT antagonist significantly reduced ERα expression in the bed nucleus of the stria terminalis (BNST), VMH, and the arcuate hypothalamic nucleus (Arc) in females and in all examined brain regions in males. In summary, the obtained data demonstrate that the early social environment could affect OXT level, which in turn leads to long-term effects on ERα expression in relevant brain regions, consequently affecting maternal behavior but not paternal behavior.

Modulation of Kalirin-7 expression by hippocampal CA1 5-HT1B receptors in spatial memory consolidation.

Serotonin 5-HT1B receptors (5-HT1BRs) are distributed in hippocampal CA1 and play a pivotal role in cognitive function. Activation of 5-HT1BRs regulates synaptic plasticity at the excitatory synapses in the hippocampus. However, the role and its underlying mechanism of 5-HT1BR activation-mediated glutamatergic synaptic plasticity in spatial memory are not fully understood. In this study, spatial memory of Sprague-Dawley (SD) rats was assessed in a Morris water maze after bilateral dorsal hippocampal CA1 infusion of the 5-HT1BR antagonist GR55562 (25 µg/µL) or agonist CP93129 (25 µg/µL). GR55562 did not affect the spatial memory acquisition but significantly increased the target quadrant preference during the memory consolidation probe performed 14 d after the training session, while CP93129 impaired the memory consolidation process. Moreover, GR55562 significantly increased, while CP93129 significantly decreased, the density of dendritic spines on the distal apical dendrites of CA1 pyramidal neurons. Furthermore, western blot experiments indicated that GR55562 significantly increased, but CP93129 significantly reduced, the expression of Kalirin-7 (Kal-7), PSD95, and GluA2/3 subunits of AMPA receptors. Our results suggest that Kal-7 and Kal-7-mediatedalteration of AMPA receptor subtype expression may play crucial roles in the impact of hippocampal CA1 5-HT1BR activation on spatial memory consolidation.

Voluntary Wheel Running Reverses Deficits in Social Behavior Induced by Chronic Social Defeat Stress in Mice: Involvement of the Dopamine System.

Voluntary exercise has been reported to have a therapeutic effect on many psychiatric disorders and social stress is known to impair social interaction. However, whether voluntary exercise could reverse deficits in social behaviors induced by chronic social defeat stress (CSDS) and the underlying mechanism remain unclear. The present study shows CSDS impaired social preference and induced social interaction deficiency in susceptible mice. Voluntary wheel running (VWR) reversed these effects. In addition, CSDS decreased the levels of tyrosine hydroxylase in the ventral tegmental area and the D2 receptor (D2R) in the nucleus accumbens (NAc) shell. These changes can be recovered by VWR. Furthermore, the recovery effect of VWR on deficits in social behaviors in CSDS mice was blocked by the microinjection of D2R antagonist raclopride into the NAc shell. Thus, these results suggest that the mechanism underlying CSDS-induced social interaction disorder might be caused by an alteration of the dopamine system. VWR may be a novel means to treat CSDS-induced deficits in social behaviors via modifying the dopamine system.

Neonatal manipulation of oxytocin influences the partner preference in mandarin voles (Microtus mandarinus).

Neonatal manipulation of oxytocin (OT) has long-term effects on behavior and physiology. The objective of this research was to determine if neonatal exposure to OT can affect partner preferences and to characterize the mechanisms underlying social behavior such as neural activities of relevant brain regions in socially monogamous mandarin voles (Microtus mandarinus). After receiving a subcutaneous injection of isotonic saline (SAL) or OT within 24h of birth, mandarin vole at 60 days of age was paired with an unfamiliar opposite sex for 24h, followed immediately by an examination of their partner preference and 30 days later by the second examination of their partner preference and Fos expression in some brain regions. The results indicated that (1) while 24h cohabitation was insufficient for both female and male SAL-treated mandarin voles to form partner preference, neonatal exposure to OT significantly facilitate female, but not male mandarin voles to form partner preference within 24h of cohabitation; (2) the maintenance of partner preference in females was suppressed by neonatal OT treatment, while neonatal OT-treated males showed significant partner preference as neonatal SAL-treated males and females; in addition, the tendency of aggression to the strangers was impaired in both females and males, and neonatal OT-treated males showed significantly higher mounting behavior to the partner; (3) in comparison with saline-treated females, OT-treated females showed a significant decrease in Fos expression in all brain regions examined in response to partner preference. Relative to saline treatment, neonatal OT treatment induced to males a significant decrease of Fos expression in the bed nucleus of the stria terminalis (BNST), the hypothalamic paraventricular nucleus (PVN) and the mediodorsal thalamic nucleus (MD) as well as a significant increase in the medial preoptic area (MPOA), the dorsal part of the lateral septal nucleus (LSD) and the central amygdaloid nucleus (CeA). These results demonstrate that neonatal OT exposure has different effects on the formation and maintenance of partner preference in mandarin voles and the latter effects possibly via OT-induced changes of the neural activities of relevant brain regions.

Pulsed electromagnetic fields alleviate streptozotocin­induced diabetic muscle atrophy.

Diabetic muscle atrophy causes a reduction of skeletal muscle size and strength, which affects normal daily activities. However, pulsed electromagnetic fields (PEMFs) can retard the atrophy of type II fibers (ActRIIB) in denervated muscles. Therefore, the purpose of the present study was to determine whether PEMFs can alleviate streptozotocin (STZ)­induced diabetic muscle atrophy. To do this, 40 Sprague­Dawley (SD) rats were randomly divided into four groups (n=10 per group): The normal control group (NC; nondiabetic rats without treatment); the diabetic mellitus group (DM; STZ­induced rats without treatment); the diabetic insulin­treated group (DT; diabetic rats on insulin treatment, 6­8 U/d twice a day for 6 weeks) as a positive control; and the diabetic PEMFs therapy group (DP; diabetic rats with PEMFs exposure treatment, 15 Hz, 1.46 mT, 30 min/day for 6 weeks). Body weight, muscle strength, muscle mass and serum insulin level were significantly increased in the DP group compared with the DM group. PEMFs also decreased the blood glucose level and altered the activity of metabolic enzymes. PEMFs significantly increased the cross­sectional area of muscle fiber. In addition, PEMFs significantly activated protein kinase B (Akt) and mammalian target of rapamycin (mTOR), and inhibited the activity of myostatin (MSTN), ActRIIB and forkhead box protein O1 (FoxO1) compared with the DM group. Thus indicating that the Akt/mTOR and Akt/FoxO1 signaling pathways may be involved in the promotion of STZ­induced diabetic muscle atrophy by PEMFs. The results of the present study suggested that PEMFs stimulation may alleviate diabetic muscle atrophy in the STZ model, and that this is associated with alterations in multiple signaling pathways in which MSTN may be an integral factor. MSTN­associated signaling pathways may provide therapeutic targets to attenuate severe diabetic muscle wasting.