Elevated Hippocampal CRMP5 Mediates Chronic Stress-Induced Cognitive Deficits by Disrupting Synaptic Plasticity, Hindering AMPAR Trafficking, and Triggering Cytokine Release.

Chronic stress is a critical risk factor for developing depression, which can impair cognitive function. However, the underlying mechanisms involved in chronic stress-induced cognitive deficits remain unclear. Emerging evidence suggests that collapsin response mediator proteins (CRMPs) are implicated in the pathogenesis of psychiatric-related disorders. Thus, the study aims to examine whether CRMPs modulate chronic stress-induced cognitive impairment. We used the chronic unpredictable stress (CUS) paradigm to mimic stressful life situations in C57BL/6 mice. In this study, we found that CUS-treated mice exhibited cognitive decline and increased hippocampal CRMP2 and CRMP5 expression. In contrast to CRMP2, CRMP5 levels strongly correlated with the severity of cognitive impairment. Decreasing hippocampal CRMP5 levels through shRNA injection rescued CUS-induced cognitive impairment, whereas increasing CRMP5 levels in control mice exacerbated memory decline after subthreshold stress treatment. Mechanistically, hippocampal CRMP5 suppression by regulating glucocorticoid receptor phosphorylation alleviates chronic stress-induced synaptic atrophy, disruption of AMPA receptor trafficking, and cytokine storms. Our findings show that hippocampal CRMP5 accumulation through GR activation disrupts synaptic plasticity, impedes AMPAR trafficking, and triggers cytokine release, thus playing a critical role in chronic stress-induced cognitive deficits.

Correlations among lean tissue index, physical activity, clinical parameters, diet quality, and nutritional status in patients receiving haemodialyses.

INTRODUCTION: Poor diet quality and malnutrition accelerate protein and energy depletion. This can result in a diminished lean tissue index (LTI) and an inability to perform daily activities, both of which increase the risk of falls and affect the quality of life. OBJECTIVE: This study investigated the correlations among LTI, physical activity (PA), clinical parameters, diet quality, and nutritional status. METHODS: A cross-sectional study design was employed. Participants in stable conditions receiving haemodialyses were enroled. LTI was measured using a body composition monitor. Three-day dietary records and demographic and clinical parameters were collected. RESULTS: In total, 104 patients receiving haemodialyses were recruited (53.8% men, aged 57.7 ± 11.78 years; dialysis duration, 7.3 ± 6.04 years). LTI was not associated with diet quality; LTI was positively correlated with sex and negatively correlated with age, dialysis duration, and fat tissue index (FTI); and lean tissue index was positively correlated with PA. Among patients with a normal LTI, the odds ratio for low-FTI was 31.04 times higher than that for high-FTI. In total, 80.8% of the participants had poor diet quality, which was mainly attributed to their excessive intake of saturated fatty acids and insufficient fruit intake. CONCLUSIONS: Although diet quality was unrelated to the LTI, the results indicated that most patients receiving haemodialyses had poor diet quality. Therefore, this topic merits further investigation.

Revealing the profound meaning of pan-firing of oolong tea - A decisive point in odor fate.

The delicate aroma of Bao-chung tea comes from oxidation, followed by fixation in the pan-firing step. Traditionally, the timing of pan-firing has been based on odor perception by tea masters and lacks relevant scientific research. Pan-firing at three different green-note intensities and three stirring sequences was used to explore the relationship between the compositions of volatile organic compounds (VOCs) before pan-firing and in the finished tea. Pan-firing decreased green leaf volatiles and increased the ratio of terpenoid volatiles. The characteristic VOCs of the finished tea were highly related to VOCs before pan-firing (R2 = 0.97). Principal component analysis revealed that the traditional judgment of the pan-firing step is based on nonanal, ß-linalool, and cis- and trans-linalool oxides. The timing of pan-firing is crucial for VOCs, and VOC composition before pan-firing can be used to predict desired tea aroma.

Association between the Serum Coenzyme Q10 Level and Seizure Control in Patients with Drug-Resistant Epilepsy.

Drug-resistant epilepsy (DRE) is a chronic neurological disorder with somatic impacts and increased risk of metabolic comorbidities. Oxidative stress might play an important role in metabolic effects and as a regulator of seizure control, while coenzyme Q10 (CoQ10) could improve insulin sensitivity through antioxidant effects. We aimed to investigate the association between CoQ10 level and clinical outcome, represented by the seizure frequency and quality of life, in DRE patients. DRE patients (N = 33) had significantly higher serum insulin levels and lower scores on the physical domain of the World Health Organization Quality of Life questionnaire (WHOQoL) than gender-age matched controls. The serum CoQ10 level (2910.4 ± 1163.7 ng/mL) was much higher in DRE patients than the normal range. Moreover, the serum CoQ10 level was significantly correlated with the seizure frequency (r = -0.412, p = 0.037) and insulin level (r = 0.409, p = 0.038). Based on stratification by insulin resistance (HOMA-IR > 2.4), the subgroup analysis showed that patients with a greater HOMA-IR had higher CoQ10 levels and lower seizure frequency, and had a significantly worse quality of life. In summary, CoQ10 could be a mediator involved in the mechanism of epilepsy and serve as a biomarker of the clinical outcome in DER patients.

Cellular senescence as a driver of cognitive decline triggered by chronic unpredictable stress.

When an individual is under stress, the undesired effect on the brain often exceeds expectations. Additionally, when stress persists for a long time, it can trigger serious health problems, particularly depression. Recent studies have revealed that depressed patients have a higher rate of brain aging than healthy subjects and that depression increases dementia risk later in life. However, it remains unknown which factors are involved in brain aging triggered by chronic stress. The most critical change during brain aging is the decline in cognitive function. In addition, cellular senescence is a stable state of cell cycle arrest that occurs because of damage and/or stress and is considered a sign of aging. We used the chronic unpredictable stress (CUS) model to mimic stressful life situations and found that, compared with nonstressed control mice, CUS-treated C57BL/6 mice exhibited depression-like behaviors and cognitive decline. Additionally, the protein expression of the senescence marker p16INK4a was increased in the hippocampus, and senescence-associated ß-galactosidase (SA-ß-gal)-positive cells were found in the hippocampal dentate gyrus (DG) in CUS-treated mice. Furthermore, the levels of SA-ß-gal or p16INK4a were strongly correlated with the severity of memory impairment in CUS-treated mice, whereas clearing senescent cells using the pharmacological senolytic cocktail dasatinib plus quercetin (D + Q) alleviated CUS-induced cognitive deficits, suggesting that targeting senescent cells may be a promising candidate approach to study chronic stress-induced cognitive decline. Our findings open new avenues for stress-related research and provide new insight into the association of chronic stress-induced cellular senescence with cognitive deficits.

Collapsin response mediator protein 5 (CRMP5) modulates susceptibility to chronic social defeat stress in mice.

Collapsin response mediator protein 5 (CRMP5), a member of the CRMP family, is expressed in the brain, particularly in the hippocampus, an area of the brain that can modulate stress responses. Social stress has a well-known detrimental effect on health and can lead to depression, but not all individuals are equally sensitive to stress. To date, researchers have not conclusively determined how social stress increases the susceptibility of the brain to depression. Here, we used the chronic social defeat stress (CSDS) model and observed higher hippocampal CRMP5 expression in stress-susceptible (SS) mice than in control and stress-resilient (RES) mice. A negative correlation was observed between the expression levels of CRMP5 and the social interaction (SI) ratio. Reduced hippocampal CRMP5 expression increased the SI ratio in SS mice, whereas CRMP5 overexpression was sufficient to induce social avoidance behaviors in control mice following exposure to subthreshold social stress induced by lentivirus-based overexpression and inducible tetracycline-on strategies to upregulate CRMP5. Interestingly, increased CRMP5 expression in SS and lenti-CRMP5-treated mice also caused serum corticosterone concentrations to increase. These findings improve our understanding of the potential mechanism by which CRMP5 triggers susceptibility to social stress, and they support the further development of therapeutic agents for the treatment of stress disorders in humans.

Increased leptin-b expression and metalloprotease expression contributed to the pyridoxine-associated toxicity in zebrafish larvae displaying seizure-like behavior.

Epilepsy is a common neurological disorder affecting people of all ages, races and ethnic backgrounds world-wide. Vitamin B6 supplementation has been widely used as an adjuvant for treating epilepsy. However, the adverse effects, including nausea and peripheral sensory neuropathy, caused by long-term and high-dose consumption of vitamin B6 have undermined the usefulness of vitamin B6 supplementation, justifying additional experimental scrutiny of vitamin B6-associated toxicity. In the current study, we found that the presence of pyridoxine, the inactive form of B6 vitamer included in most nutrient supplements, increased the mortality of the larvae displaying chemical-induced epilepsy. The expression of leptin-b, one zebrafish ortholog of human leptin, was significantly increased in the larvae displaying seizures. Increased leptin-b expression alleviated larval seizure-like behavior when exposed to epilepsy inducer, but also increased larval mortality in the presence of pyridoxine. Meanwhile, elevated adam17 and mmp13 mRNA level were found in the larvae simultaneously exposed to epilepsy-inducer and pyridoxine. Adding TNF-α inhibitor and mmp13 inhibitor effectively improved the survival of larvae injected with leptin-b mRNA and exposed to pyridoxine subsequently. We conclude that increased leptin-b and metalloprotease expression contributed, at least partly, to the pyridoxine-associated toxicity observed in larvae displaying seizures.

An Open Pilot Study of the Effect and Tolerability of Add-On Multivitamin Therapy in Patients with Intractable Focal Epilepsy.

Observational studies have investigated the potential modulatory effect of neuronal excitability by vitamins in epilepsy. We aimed to investigate whether the addition of multivitamin therapy (B6/B9, D, E and Q) to regular antiepileptic drug therapy could ameliorate seizures in patients with refractory focal epilepsy. We conducted a prospective cohort open study to investigate the effect and tolerability of add-on multivitamin therapy (daily dose: B6 100 mg, B9 5 mg, D 1000 IU, E 400 IU and coenzyme Q10 100 mg) in patients with intractable focal epilepsy. All patients had effect and safety assessments at baseline and after one, three and six months of the supplementation. Thirty patients (11 men and 19 women) with a mean age of 42.37 ± 9.40 years were recruited and four patients discontinued. The seizure frequency significantly decreased after the six-month supplementation (9.04 ± 18.16/month and 2.06 ± 3.89/month, p = 0.045). At the final visit, 62.5% of the patients showed a ≥50% reduction in seizure frequency, and 12.5% were seizure-free. As to safety and tolerability, most patients did not experience significant adverse events, although three patients reported seizure worsening. In conclusion, this pilot study demonstrated the therapeutic potential and essentially good tolerability of add-on multivitamin therapy in patients with refractory focal epilepsy.

Physalin A attenuates inflammation through down-regulating c-Jun NH2 kinase phosphorylation/Activator Protein 1 activation and up-regulating the antioxidant activity.

Physalin A (PA), a withanolide, was isolated from Physalis angulata L. In this study, it is shown that PA can inhibit the production of inflammatory cytokines such as PGE2, NO, IL-1ß, IL-6, and TNF-α in LPS-induced RAW 264.7 cells. Furthermore, the results indicated that PA suppressed the IκB/NF-κB and JNK/ AP-1 inflammatory signaling pathways and inhibited the levels of pro-inflammatory factors iNOS and COX-2 in LPS-stimulated RAW 264.7 cells. In the carrageenan-induced mouse hind paw edema study, PA was shown to inhibit the production of inflammatory mediators such as NO, MDA, and TNF-α production. Conversely, the antioxidant factor levels of SOD, CAT, and GPx were all increased by the treated PA. According to the data, we are suggesting that the anti-inflammatory effects of PA may be through the suppressions of the JNK/AP-1 and IκB/NF-κB signaling pathways and up-regulation of the anti-oxidative activity.

Relative D3 vitamin deficiency and consequent cognitive impairment in an animal model of Alzheimer's disease: Potential involvement of collapsin response mediator protein-2.

Alzheimer's disease (AD) starts with memory impairments that can be observed before the appearance of significant neuropathology; thus, identifying mechanisms to stop AD progression is an urgent priority. Epidemiological and clinical data show that the consequences of vitamin D deficiency are relevant to disease risk and can be observed in the progression of many diseases, especially AD, whereas higher serum levels of vitamin D are associated with better cognitive test performance. However, the potential therapeutic strategy and underlying mechanisms of vitamin D supplementation against AD still need to be further investigated. In the present study, we found that 3xTg-AD mice with vitamin D supplementation exhibited an increase in serum vitamin D concentrations and improved cognition. We measured serum vitamin D binding protein (VDBP) concentrations and found that serum VDBP levels were increased in 3xTg-AD mice compared to B6129S control mice, but there was no significant difference between control- and vitamin D-treated 3xTg-AD groups. The vitamin D-mediated memory improvement may be accompanied by the suppression of increased hippocampal collapsin response mediator protein-2 (CRMP2) phosphorylation, and the restoration of CRMP2 phosphorylation by okadaic acid (OA) could abolish the beneficial effects of vitamin D. In addition, we found that CRMP2 was associated with NR2B and PSD-95 in 3xTg-AD mice with vitamin D supplementation. This CRMP2-NR2B interaction could be disrupted by a TAT-CBD3 peptide or OA, leading to attenuated memory protection in vitamin D-treated 3xTg-AD mice. Therefore, CRMP2 may be involved in vitamin D-mediated memory improvement in AD.

Collapsin response mediator protein 5 (CRMP5) causes social deficits and accelerates memory loss in an animal model of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by several behavioral disturbances, especially cognitive decline and deficits in social competence. Previous studies revealed that decreased social activity would accelerate AD progression, whereas enhanced social interaction could rescue AD-induced memory impairment. Collapsin response mediator protein 5 (CRMP5), which belongs to a family of cytosolic proteins, is abundantly expressed in the brain and is involved in the regulation of neurodevelopment and the pathology of several neuropsychiatric diseases. However, the functions of CRMP5 in AD are still unclear. Here, we demonstrated that 9-month-old 3xTg-AD mice exhibited social behavioral deficits and increased hippocampal CRMP5 levels compared to control (B6129S) mice. Knockdown of CRMP5 reversed the social deficits in 9-month-old 3xTg-AD mice, whereas CRMP5 overexpression decreased social interaction in both 3xTg-AD and control mice at 6 months of age. Interestingly, decreased expression of CRMP5 rescued AD-induced memory impairment, but overexpression of CRMP5 accelerated memory loss only in 3xTg-AD mice. In addition, we found that CRMP5 could regulate surface GluA2 and GluA2 S880 phosphorylation. These results suggest that CRMP5 regulates social behavior via modulation of surface GluA2 trafficking and affects memory performance in 3xTg-AD mice.

Myostatin Is Associated With Cognitive Decline in an Animal Model of Alzheimer's Disease.

With aging, there are progressive functional declines in multiple organ systems. One of the major physiological problems observed in aged people is skeletal muscle loss. This age-related muscle loss causes muscle weakness and disability, which in turn might reduce the quality of life in older adults and lead to the progression of several diseases, particularly Alzheimer's disease (AD). Some researchers have hypothesized that loss of muscle mass and strength is linked to the risk of developing AD. In addition, unintended weight loss often occurs in AD patients and might reflect dementia severity. However, the causal relationship between muscle atrophy and cognitive deficits in AD is unclear. We found that double transgenic amyloid precursor protein and presenilin 1 (APP/PS1) mice that co-express APP and PS1 at older ages exhibited lower body weight and lean tissue mass than sex- and age-matched wild-type (WT) mice. In addition, muscle atrophy and the extent of memory decline were strongly correlated in APP/PS1 mice. Myostatin levels in the gastrocnemius (GAS) muscle of 12-month-old APP/PS1 mice were elevated. We determined that the cellular and molecular mechanism of muscle atrophy was through the ubiquitin-proteasome pathway. Furthermore, myostatin knockdown in the GAS muscles increased grip strength and muscle mass, leading to memory improvement in myostatin short-hairpin RNA-treated APP/PS1 mice. We conclude that high-level myostatin expression might mediate or trigger muscle atrophy and cognitive deficits.

Impact of social relationships on Alzheimer's memory impairment: mechanistic studies.

Alzheimer's disease (AD) is characterized by progressive memory and neuronal loss culminating in cognitive impairment that not only affects a person's living ability but also becomes a society's as well as a family's economic burden. AD is the most common form of dementia in older persons. It is expected that the number of people with AD dementia will increase dramatically in the next 30 years, projecting to 75 million in 2030 and 131.5 million in 2050 worldwide. So far, no sufficient evidence is available to support that any medicine is able to prevent or reverse the progression of the disease. Early studies have shown that social environment, particularly social relationships, can affect one's behavior and mental health. A study analyzing the correlation between loneliness and risk of developing AD revealed that lonely persons had higher risk of AD compared with persons who were not lonely. On the other hand, it has been reported that we can prevent cognitive decline and delay the onset of AD if we keep mentally active and frequently participate in social activities. In this review, we focus on the impact of social behaviors on the progression of cognitive deficit in animal models of AD with a particular emphasis on a mechanistic scheme that explains how social isolation exacerbates cognitive impairment and how social interaction with conspecifics rescues AD patients' memory deficit.

[Using Interdisciplinary Cooperation to Improve the Rate of Proper Performance of a Hand Exercise Among Hemodialysis Patients With Arteriovenous Fistula Construction].

BACKGROUND & PROBLEMS: Patients who undergo new arteriovenous fistula (AVF) construction as part of their hemodialysis treatment program are required to perform hand exercises properly in order to maintain AVF function. However, poor performance of these hand exercises currently results in the failure of many patients to preserve AVF function. PURPOSE: To increase the rate of performing this hand exercise properly from 55% to 80%. RESOLUTION: A comprehensive investigation identified the following five main problems: (a) Insufficient muscular endurance; (b) Resistance was not labeled on the ball; (c) Difficulties with maintaining a grip on the ball during the exercise; (d) Lack of standardized education procedures; and (e) Nurses lack latest knowledge on the hand exercise. The strategies used to improve the situation included: (a) Interdisciplinary team cooperation with physiotherapists to design individualized resistance training regimens; (b) Exercise tool improvement; (c) Standardized AVF care; (d) Continuous education for nursing staffs; and (e) Seed teacher program for hand exercise. RESULTS: The rate of proper hand exercise performance increased from 55% to 93%. CONCLUSIONS: This nursing project involved an interdisciplinary team that included physiotherapists in order to successfully improve the rate at which the hand exercise was performed properly. This positive experience may be applied to other hemodialysis departments in the treatment of patients with AVF.

Co-housing reverses memory decline by epigenetic regulation of brain-derived neurotrophic factor expression in an animal model of Alzheimer's disease.

Co-housing with a company exerts profound effects on memory decline in animal model of Alzheimer's disease (AD). Recently, we found that APP/PS1 mice of 9-month-old improved their memories after co-housing with wide-type mice for 3months by increasing hippocampal brain-derived neurotrophic factor (BDNF) expression. However, the mechanism of how co-housing could induce BDNF expression remains elusive. Here we examined epigenetic changes in the mouse hippocampus that accompanied the co-housing-induced memory improvement. We found that the level of histone deacetylase 2 (HDAC2), but not that of HDAC1, was significantly lower in the memory improved mice than in the control and memory un-improved APP/PS1 mice after co-housing. Knockdown of Hdac2 resulted in a higher freezing response after co-housing. Conversely, over-expression of HDAC2 blocked co-housing-induced memory improvement. The level of Bdnf exon IV mRNA increased significantly after knockdown of Hdac2. ChIP assay revealed a decreased occupancy of HDAC2 in the promoter region of Bdnf exon IV of memory improved mice but not memory un-improved and control APP/PS1 mice. Consistently, the acetylation of histone 3 on Lys 9 (H3K9) and histone 4 on Lys12 (H4K12) increased significantly in the promoter region of Bdnf exon IV. These results suggest HDAC2 expression is reduced after co-housing resulting in a decreased occupancy of HDAC2 and increased histone H3K9 and H4K12 acetylation in the promoter region of Bdnf exon IV, leading to increased BDNF expression in the hippocampus that improves memory.

Epigenetic regulation of BDNF in the learned helplessness-induced animal model of depression.

Major depressive disorder (MDD), one of the most common mental disorders, is a significant risk factor for suicide and causes a low quality of life for many people. However, the causes and underlying mechanism of depression remain elusive. In the current work, we investigated epigenetic regulation of BDNF in the learned helplessness-induced animal model of depression. Mice were exposed to inescapable stress and divided into learned helplessness (LH) and resilient (LH-R) groups depending on the number they failed to escape. We found that the LH group had longer immobility duration in the forced swimming test (FST) and tail suspension tests (TST), which is consistent with a depression-related phenotype. Western blotting analysis and enzyme-linked immunosorbent assay (ELISA) revealed that the LH group had lower BDNF expression than that of the LH-R group. The LH group consistently had lower BDNF mRNA levels, as detected by qPCR assay. In addition, we found BDNF exon IV was down-regulated in the LH group. Intraperitoneal injection of imipramine or histone deacetylase inhibitors (HDACi) to the LH mice for 14 consecutive days ameliorated depression-like behaviors and reversed the decrease in BDNF. The expression of HDAC5 was up-regulated in the LH mice, and a ChIP assay revealed that the level of HDAC5 binding to the promoter region of BDNF exon IV was higher than that seen in other groups. Knockdown of HDAC5 reduced depression-like behaviors in the LH mice. Taken together, these results suggest that epigenetic regulation of BDNF by HDAC5 plays an important role in the learned helplessness model of depression.

Sonic hedgehog signaling regulates amygdalar neurogenesis and extinction of fear memory.

It is now recognized that neurogenesis occurs throughout life predominantly in the subgranular zone (SGZ) of the hippocampus and the subventricular zone (SVZ) of the lateral ventricle. In the present study, we investigated the relationship between neurogenesis in the amygdala and extinction of fear memory. Mice received 15 tone-footshock pairings. Twenty-four hours after training, the mice were given 15 tone-alone trials (extinction training) once per day for 7 days. Two hours before extinction training, the mice were injected intraperitoneally with 5-bromo-3-deoxyuridine (BrdU). BrdU-positive and NeuN-positive cells were analyzed 52 days after the training. A group of mice that received tone-footshock pairings but no extinction training served as controls (FC+No-Ext). The number of BrdU(+)/NeuN(+) cells was significantly higher in the extinction (FC+Ext) than in the FC+No-Ext mice. Proliferation inhibitor methylazoxymethanol acetate (MAM) or DNA synthesis inhibitor cytosine arabinoside (Ara-C) reduced neurogenesis and retarded extinction. Silencing Sonic hedgehog (Shh) gene with short hairpin interfering RNA (shRNA) by means of a retrovirus expression system to knockdown Shh specifically in the mitotic neurons reduced neurogenesis and retarded extinction. By contrast, over-expression of Shh increased neurogenesis and facilitated extinction. These results suggest that amygdala neurogenesis and Shh signaling are involved in the extinction of fear memory.

Social isolation-induced increase in NMDA receptors in the hippocampus exacerbates emotional dysregulation in mice.

Epidemiological studies have shown that early life adverse events have long-term effects on the susceptibility to subsequent stress exposure in adolescence, but the precise mechanism is unclear. In the present study, mice on postnatal day 21-28 were randomly assigned to either a group or isolated cages for 8 weeks. The socially isolated (SI) mice exhibited a higher level of spontaneous locomotor activity, a longer duration of immobility in the forced swimming test (FST), significantly less prepulse inhibition (PPI) and an increase in aggressive (but not attack) behavior. However, acute stress markedly exacerbated the attack counts of the SI mice but did not affect the group housing (GH) mice. SI mice exhibited higher synaptosomal NR2A and NR2B levels in the hippocampus as compared to the GH mice. Whole-cell patch clamp recordings of CA1 neurons in hippocampal slices showed that the SI mice exhibited a higher input-output relationship of NMDAR-EPSCs as compared to the GH mice. Application of the NR2B -specific antagonist ifenprodil produced a greater attenuating effect on NMDAR-EPSCs in slices from the SI mice. NMDAR EPSCs recorded from the SI mice had a slower deactivation kinetic. MK-801, CPP and ifenprodil, the NMDA antagonists, reversed acute stress-induced exaggeration of aggressive and depressive behaviors. Furthermore, acute stress-induced exacerbation of attack behavior in the SI mice was abolished after the knockdown of NR2B expression. These results suggest that social isolation-induced increased expression of NMDA receptors in the hippocampus involves stress exacerbation of aggressive behaviors. Amelioration of aggressive behaviors by NMDA antagonists may open a new avenue for the treatment of psychopathologies that involve outbursts of emotional aggression in neglected children.

Social interaction rescues memory deficit in an animal model of Alzheimer's disease by increasing BDNF-dependent hippocampal neurogenesis.

It has been recognized that the risk of cognitive decline during aging can be reduced if one maintains strong social connections, yet the neural events underlying this beneficial effect have not been rigorously studied. Here, we show that amyloid precursor protein (APP) and presenilin 1 (PS1) double-transgenic (APP/PS1) mice demonstrate improvement in memory after they are cohoused with wild-type mice. The improvement was associated with increased protein and mRNA levels of BDNF in the hippocampus. Concomitantly, the number of BrdU(+)/NeuN(+) cells in the hippocampal dentate gyrus was significantly elevated after cohousing. Methylazoxymethanol acetate, a cell proliferation blocker, markedly reduced BrdU(+) and BrdU/NeuN(+) cells and abolished the effect of social interaction. Selective ablation of mitotic neurons using diphtheria toxin (DT) and a retrovirus vector encoding DT receptor abolished the beneficial effect of cohousing. Knockdown of BDNF by shRNA transfection blocked, whereas overexpression of BDNF mimicked the memory-improving effect. A tropomyosin-related kinase B agonist, 7,8-dihydroxyflavone, occluded the effect of social interaction. These results demonstrate that increased BDNF expression and neurogenesis in the hippocampus after cohousing underlie the reversal of memory deficit in APP/PS1 mice.

Learning induces sonic hedgehog signaling in the amygdala which promotes neurogenesis and long-term memory formation.

BACKGROUND: It is known that neurogenesis occurs throughout the life mostly in the subgranular zone of the hippocampus and the subventricular zone of the lateral ventricle. We investigated whether neurogenesis occurred in the amygdala and its function in fear memory formation. METHODS: For detection of newborn neurons, mice were injected intraperitoneally with 5-bromo-2'-deoxyuridine (BrdU) 2h before receiving 15 tone-footshock pairings, and newborn neurons were analyzed 14 and 42 days after training. To determine the relationship between neurogenesis and memory formation, mice were given a proliferation inhibitor methylazoxymethanol (MAM) or a DNA synthesis inhibitor cytosine arabinoside (Ara-C). To test whether sonic hedgehog (Shh) signaling was required for neurogenesis, Shh-small hairpin-interfering RNA (shRNA) was inserted into a retroviral vector (Retro-Shh-shRNA). RESULTS: The number of BrdU(+)/Neuronal nuclei (NeuN)(+) cells was significantly higher in the conditioned mice, suggesting that association of tone with footshock induced neurogenesis. MAM and Ara-C markedly reduced neurogenesis and impaired fear memory formation. Shh, its receptor patched 1 (Ptc1), and transcription factor Gli1 protein levels increased at 1 day and returned to baseline at 7 days after fear conditioning. Retro-Shh-shRNA, which knocked down Shh specifically in the mitotic neurons, reduced the number of BrdU(+)/NeuN(+) cells and decreased freezing responses. CONCLUSIONS: These results suggest that fear learning induces Shh signaling activation in the amygdala, which promotes neurogenesis and fear memory formation.