Social experiences switch states of memory engrams through regulating hippocampal Rac1 activity.

In pathological or artificial conditions, memory can be formed as silenced engrams that are unavailable for retrieval by presenting conditioned stimuli but can be artificially switched into the latent state so that natural recall is allowed. However, it remains unclear whether such different states of engrams bear any physiological significance and can be switched through physiological mechanisms. Here, we show that an acute social reward experience switches the silent memory engram into the latent state. Conversely, an acute social stress causes transient forgetting via turning a latent memory engram into a silent state. Such emotion-driven bidirectional switching between latent and silent states of engrams is mediated through regulation of Rac1 activity­dependent reversible forgetting in the hippocampus, as stress-activated Rac1 suppresses retrieval, while reward recovers silenced memory under amnesia by inhibiting Rac1. Thus, data presented reveal hippocampal Rac1 activity as the basis for emotion-mediated switching between latent and silent engrams to achieve emotion-driven behavioral flexibility.

Hypoxic postconditioning promotes mitophagy against transient global cerebral ischemia via PINK1/Parkin-induced mitochondrial ubiquitination in adult rats.

Mitophagy alleviates neuronal damage after cerebral ischemia by selectively removing dysfunctional mitochondria. Phosphatase and tensin homolog (PTEN) induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy is the most well-known type of mitophagy. However, little is known about the role of PINK1/Parkin-mediated mitophagy in ischemic tolerance induced by hypoxic postconditioning (HPC) with 8% O2 against transient global cerebral ischemia (tGCI). Hence, we aimed to test the hypothesis that HPC-mediated PINK1/Parkin-induced mitochondrial ubiquitination and promotes mitophagy, thus exerting neuroprotection in the hippocampal CA1 subregion against tGCI. We found that mitochondrial clearance was disturbed at the late phase of reperfusion after tGCI, which was reversed by HPC, as evidenced by the reduction of the translocase of outer mitochondrial membrane 20 homologs (TOMM20), translocase of inner mitochondrial membrane 23 (TIMM23) and heat shock protein 60 (HSP60) in CA1 after HPC. In addition, HPC further increased the ratio of LC3II/I in mitochondrial fraction and promoted the formation of mitophagosomes in CA1 neurons after tGCI. The administration of lysosome inhibitor chloroquine (CQ) intraperitoneally or mitophagy inhibitor (Mdivi-1) intracerebroventricularly abrogated HPC-induced mitochondrial turnover and neuroprotection in CA1 after tGCI. We also found that HPC activated PINK1/Parkin pathway after tGCI, as shown by the augment of mitochondrial PINK1 and Parkin and the promotion of mitochondrial ubiquitination in CA1. In addition, PINK1 or Parkin knockdown with small-interfering RNA (siRNA) suppressed the activation of PINK1/Parkin pathway and hampered mitochondrial clearance and attenuated neuroprotection induced by HPC, whereas PINK1 overexpression promoted PINK1/Parkin-mediated mitophagy and ameliorated neuronal damage in CA1 after tGCI. Taken together, the new finding in this study is that HPC-induced neuroprotection against tGCI through promoting mitophagy mediated by PINK1/Parkin-dependent pathway.

Exercise Improved the Anti-Epileptic Effect of Carbamazepine through GABA Enhancement in Epileptic Rats.

Carbamazepine (CBZ) is an anticonvulsant drug that usually is used for the treatment of seizures. The anti-epileptic and the anti-epileptogenic effect of exercise has been reported, as well. This study was aimed to evaluate the synergic effect of combined therapy of exercise and CBZ in epileptic rats, as well as the alternation of the GABA pathway as a possible involved mechanism. The seizure was induced by pentylenetetrazol (PTZ) injection. Animals were divided into sham, seizure, exercise (EX), CBZ (25, 50 and 75), EX + CBZ (25, 50 and 75). Treadmill forced running for 30 min has been considered as the exercise 5 days per week for four weeks. CBZ was injected in doses of 25, 50 and 75 mg/kg, half an hour before seizure induction and 5 h after doing exercise in the animals forced to exercise. Seizure severity reduced and latency increased in the EX + CBZ (25) and EX + CBZ (50) groups compared to the seizure group. The distribution of GAD65 in both hippocampal CA1 and CA3 areas increased in the EX + CBZ (75) group. GABAA receptor α1 was up-regulated in the CA3 area of the EX + CBZ (75) group. The distribution of GAD65 in the cortical area increased in EX, EX + CBZ (50), CBZ (75) and EX + CBZ (75) groups. GABAA receptor α1 was up-regulated in the neocortex of EX + CBZ (50), CBZ (75) and EX + CBZ (75) groups. Our findings suggested that exercise has improved the efficacy of CBZ and reduced the anti-epileptic dose. The enhancement of GABA signaling might be involved in the synergistic effect of exercise and CBZ.

Hippocampal Aromatase Knockdown Aggravates Ovariectomy-Induced Spatial Memory Impairment, Aß Accumulation and Neural Plasticity Deficiency in Adult Female Mice.

Ovarian estrogens (mainly 17ß estradiol, E2) have been involved in the regulation of the structure of hippocampus, the center of spatial memory. In recent years, high levels of aromatase (AROM), the estrogen synthase, has been localized in hippocampus; and this hippocampus-derived E2 seems to be functional in synaptic plasticity and spatial memory as ovarian E2 does. However, the contribution of ovarian E2 and hippocampal E2 to spatial memory and neural plasticity remains unclear. In this study, AROM-specific RNA interference AAVs (shAROM) were constructed and injected into the hippocampus of control or ovariectomized (OVX) mice. Four weeks later the spatial learning and memory behavior was examined with Morris water maze, the expression of hippocampal Aß related proteins, selected synaptic proteins and CA1 synapse density, actin polymerization related proteins and CA1 spine density were also examined. The results showed that while OVX and hippocampal shAROM contributed similarly to most of the parameters examined, shAROM induced more increase in BACE1 (amyloidogenic ß-secretase), more decrease in neprilysin (Aß remover) and Profilin-1 (actin polymerization inducer). More importantly, combined OVX and shAROM treatment displayed most significant impairment of spatial learning and memory as well as decrease in synaptic plasticity compared to OVX or shAROM alone. In conclusion, the above results clearly demonstrated the crucial role of hippocampal E2 in the regulation of the structure and function of hippocampus besides ovarian E2, indicating that hippocampal E2 content should also be taken into consideration during estrogenic replacement.

The Effect of Allopregnanolone on Enzymatic Activity of the DNA Base Excision Repair Pathway in the Sheep Hippocampus and Amygdala under Natural and Stressful Conditions.

The neurosteroid allopregnanolone (AL) has many beneficial functions in the brain. This study tested the hypothesis that AL administered for three days into the third brain ventricle would affect the enzymatic activity of the DNA base excision repair (BER) pathway in the hippocampal CA1 and CA3 fields and the central amygdala in luteal-phase sheep under both natural and stressful conditions. Acute stressful stimuli, including isolation and partial movement restriction, were used on the last day of infusion. The results showed that stressful stimuli increased N-methylpurine DNA glycosylase (MPG), thymine DNA glycosylase (TDG), 8-oxoguanine glycosylase (OGG1), and AP-endonuclease 1 (APE1) mRNA expression, as well as repair activities for 1,N6-ethenoadenine (εA), 3,N4-ethenocytosine (εC), and 8-oxoguanine (8-oxoG) compared to controls. The stimulated events were lower in stressed and AL-treated sheep compared to sheep that were only stressed (except MPG mRNA expression in the CA1 and amygdala, as well as TDG mRNA expression in the CA1). AL alone reduced mRNA expression of all DNA repair enzymes (except TDG in the amygdala) relative to controls and other groups. DNA repair activities varied depending on the tissue-AL alone stimulated the excision of εA in the amygdala, εC in the CA3 and amygdala, and 8-oxoG in all tissues studied compared to controls. However, the excision efficiency of lesioned bases in the AL group was lower than in the stressed and stressed and AL-treated groups, with the exception of εA in the amygdala. In conclusion, the presented modulating effect of AL on the synthesis of BER pathway enzymes and their repair capacity, both under natural and stressful conditions, indicates another functional role of this neurosteroid in brain structures.

Exercise-induced Nitric Oxide Contributes to Spatial Memory and Hippocampal Capillaries in Rats.

Exercise has been argued to improve cognitive function in both humans and rodents. Angiogenesis significantly contributes to brain health, including cognition. The hippocampus is a crucial brain region for cognitive function. However, studies quantifying the capillary changes in the hippocampus after running exercise are lacking. Moreover, the molecular details underlying the effects of running exercise remain poorly understood. We show that endogenous nitric oxide contributes to the beneficial effects of running exercise on cognition and hippocampal capillaries. Four weeks of running exercise significantly improved spatial memory ability and increased the number of capillaries in the cornu ammonis 1 subfield and dentate gyrus of Sprague-Dawley rats. Running exercise also significantly increased nitric oxide synthase activity and nitric oxide content in the rat hippocampus. After blocking the synthesis of endogenous nitric oxide by lateral ventricular injection of NG-nitro-L-arginine methyl ester, a nonspecific nitric oxide synthase inhibitor, the protective effect of running exercise on spatial memory was eliminated. The protective effect of running exercise on angiogenesis in the cornu ammonis 1 subfield and dentate gyrus of rats was also absent after nitric oxide synthase inhibition. Therefore, during running excise, endogenous nitric oxide may contribute to regulating spatial memory ability and angiogenesis in cornu ammonis 1 subfield and dentate gyrus of the hippocampus.

Conditional Dnmt3b deletion in hippocampal dCA1 impairs recognition memory.

AIM: Active changes in neuronal DNA methylation and demethylation appear to act as controllers of synaptic scaling and glutamate receptor trafficking in learning and memory formation. DNA methyltransferases (DNMTs), including proteins encoded by Dnmt1, Dnmt3a and Dnmt3b, are dominant enzymes carrying out DNA methylation. Our previous study demonstrated the important roles that DNMT1 and DNMT3a play in synaptic function and memory. In this study, we aim to explore the role of DNMT3b and its-mediated DNA methylation in memory processes. METHODS: Dnmt3b was knocked down specifically in dorsal CA1 neurons of adult mice hippocampus by AAV-syn-Cre-GFP virus injection. Behavioral tests were used to evaluate memory performance. Gene expression microarray analysis followed by quantitative RT-PCR were performed to find differential expression genes. RESULTS: Dnmt3bflox/flox mice receiving Cre-virus infection showed impaired novel object-place recognition (NPR) and normal novel object recognition (NOR), in comparison to mice receiving control GFP-virus infection. Microarray analysis revealed differential expression of K+ channel subunits in the hippocampus of Dnmt3bflox/flox mice receiving Cre-virus injection. Increased Kcne2 expression was confirmed by following qRT-PCR analysis. We also found that NPR training and testing induced up-regulation of hippocampal Dnmt1 and Dnmt3a mRNA expression in control mice, but not in Cre-virus injected mice. Our findings thus demonstrate that conditional Dnmt3b deletion in a sub-region of the hippocampus impairs a specific form of recognition memory that is hippocampus-dependent.

BACE1 partial deletion induces synaptic plasticity deficit in adult mice.

BACE1 is the first enzyme involved in APP processing, thus it is a strong therapeutic target candidate for Alzheimer's disease. The observation of deleterious phenotypes in BACE1 Knock-out (KO) mouse models (germline and conditional) raised some concerns on the safety and tolerability of BACE1 inhibition. Here, we have employed a tamoxifen inducible BACE1 conditional Knock-out (cKO) mouse model to achieve a controlled partial depletion of BACE1 in adult mice. Biochemical and behavioural characterization was performed at two time points: 4-5 months (young mice) and 12-13 months (aged mice). A ~50% to ~70% BACE1 protein reduction in hippocampus and cortex, respectively, induced a significant reduction of BACE1 substrates processing and decrease of Aßx-40 levels at both ages. Hippocampal axonal guidance and peripheral nerve myelination were not affected. Aged mice displayed a CA1 long-term potentiation (LTP) deficit that was not associated with memory impairment. Our findings indicate that numerous phenotypes observed in germline BACE1 KO reflect a fundamental role of BACE1 during development while other phenotypes, observed in adult cKO, may be absent when partially rather than completely deleting BACE1. However, we demonstrated that partial depletion of BACE1 still induces CA1 LTP impairment, supporting a role of BACE1 in synaptic plasticity in adulthood.

Effect of oleuropein on morphine-induced hippocampus neurotoxicity and memory impairments in rats.

Oleuropein, as an olive leaf extract antioxidant polyphenol, has been reported to be a free radical scavenger. This study was done to investigate the effects of oleuropein, against morphine-induced hippocampus neurotoxicity and memory impairment in rats. The Morris water maze (MWM) test was used to assess the effect of oleuropein (5, 15, and 30 mg/kg, i.p., co-administrated with morphine) on spatial learning and memory of male Wistar rats which were treated with morphine sulfate (45 mg/kg, s.c., 4 weeks). In order to evaluate the cleaved caspase-3, Bax, and Bcl2 protein expression (as biochemical markers of apoptosis) in CA1 area of hippocampus tissue, the western blot test was used. Also, to evaluate the oxidative stress status of hippocampus CA1 area tissue, the malondialdehyde (MDA) level, superoxide dismutase (SOD) activity, and glutathione peroxidase (GPx) activity were assessed. The data showed that oleuropein treatment (15 and 30 mg/kg) improves the spatial learning and memory impairments in morphine-treated animals. Also, oleuropein treatment decreased the apoptosis and oxidative stress levels in the hippocampus CA1 area of morphine-treated rats. Oleuropein can prevent the spatial learning and memory impairments in morphine-treated rats. Molecular mechanisms underlying the observed effects could be at least partially related to the inhibition of neuronal apoptosis and oxidative stress in the hippocampus CA1 area of morphine-treated rats.

A protein phosphatase 2A deficit in the hippocampal CA1 area impairs memory extinction.

Protein phosphorylation plays an important role in learning and memory. Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase involved in the regulation of neural synaptic plasticity. Here, to determine if PP2A is necessary for successful learning and memory, we have utilized a Tg (Camk2a-cre) T29-2Stl mice to specific knock down the expression of hippocampal PP2A in mice. By analysing behavioural, we observed that loss of PP2A in the hippocampal CA1 area did not affect the formation of memory but impaired contextual fear memory extinction. We use the electrophysiological recording to find the synaptic mechanisms. The results showed that the basic synapse transmission and synaptic plasticity of PP2A conditional knockout (CKO) mice were impaired. Moreover, PP2A CKO mice exhibited a saturating long-term potentiation inducted by strong theta burst stimulation but no depotentiation after low-frequency stimulation. Taken together, our results provide the evidence that PP2A is involved in synaptic transmission and hippocampus-dependent memory extinction.

Overexpression of activated CaMKII in the CA1 hippocampus impairs context discrimination, but not contextual conditioning.

Calcium/Calmodulin-dependent protein kinase II (CaMKII) plays a key role in the molecular mechanism of memory formation. CaMKII is known to be activated specifically in the activated spines during memory formation. However, it is unclear whether the specific activation of CaMKII is necessary for encoding information. Here, we overexpressed active form of CaMKII (CaMKII*) in the hippocampal CA1 region to activate CaMKII nonspecifically. Moreover, we examined context-discrimination performance of mice. We found that the mice with overexpression of CaMKII* showed impaired context-discrimination ability, while the contextual fear conditioning remained intact. These results indicate that spatial specificity of CaMKII activation is necessary for context discrimination.

Hypoxic preconditioning attenuates necroptotic neuronal death induced by global cerebral ischemia via Drp1-dependent signaling pathway mediated by CaMKIIα inactivation in adult rats.

Hypoxic preconditioning (HPC) alleviates the selective and delayed neuronal death in the hippocampal CA1 region induced by transient global cerebral ischemia (tGCI). This type of cell death may include different programmed cell death mechanisms, namely, apoptosis and necroptosis. Although apoptotic signaling is well defined, the mechanisms that underlie neuronal necroptosis are yet to be fully elucidated. In this study, we investigated whether HPC protects neurons from cerebral ischemia-induced necroptosis. We observed that tGCI up-regulated the expression of receptor-interacting protein (RIP) 3 and increased the interaction of RIP1-RIP3 in CA1 at the early stage of reperfusion. The pretreatment with HPC or necrostatin-1 decreased the expression of RIP3 and the formation of RIP1-RIP3 after tGCI. We also found that HPC decreased the expression and the activity of caspase-8 in CA1 after tGCI, and notably, the pretreatment with Z-VAD-FMK, a pan-caspase inhibitor, did not trigger necroptosis but attenuated the tGCI-induced neuronal damage. Furthermore, we demonstrated that HPC decreased the activation of calcium-calmodulin kinase (CaMK) IIα and the interaction of RIP1 and CaMKIIα induced by tGCI. Intriguingly, the pretreatment with a CaMKs inhibitor KN-93 before tGCI resulted in significantly reduced RIP1-3 interaction and tGCI-induced neuronal damage. Finally, we ascertained that HPC prevented the dephosphorylation of dynamin-related protein 1 (Drp1)-Ser637 (serine 637) and inhibited the translocation of Drp1 to mitochondria induced by tGCI. Importantly, the treatment with a Drp1 inhibitor Mdivi-1 or necrostatin-1 before tGCI also abolished Drp1 dephosphorylation at Ser637 and mitochondrial translocation. Taken together, our results highlight that HPC attenuates necroptotic neuronal death induced by tGCI via Drp1-dependent mitochondrial signaling pathways mediated by CaMKIIα inactivation.-Zhan, L., Lu, Z., Zhu, X., Xu, W., Li, L., Li, X., Chen, S., Sun, W., Xu, E. Hypoxic preconditioning attenuates necroptotic neuronal death induced by global cerebral ischemia via Drp1-dependent signaling pathway mediated by CaMKIIα inactivation in adult rats.

The potential role of HO-1 in regulating the MLK3-MKK7-JNK3 module scaffolded by JIP1 during cerebral ischemia/reperfusion in rats.

Heme oxygenase (HO-1), which may be induced by Cobaltic protoporphyrin IX chloride (CoPPIX) or Rosiglitazone (Ros), is a neuroprotective agent that effectively reduces ischemic stroke. Previous studies have shown that the neuroprotective mechanisms of HO-1 are related to JNK signaling. The expression of HO-1 protects cells from death through the JNK signaling pathway. This study aimed to ascertain whether the neuroprotective effect of HO-1 depends on the assembly of the MLK3-MKK7-JNK3 signaling module scaffolded by JIP1 and further influences the JNK signal transmission through HO-1. Prior to the ischemia-reperfusion experiment, CoPPIX was injected through the lateral ventricle for 5 consecutive days or Ros was administered via intraperitoneal administration in the week prior to transient ischemia. Our results demonstrated that HO-1 could inhibit the assembly of the MLK3-MKK7-JNK3 signaling module scaffolded by JIP1 and could ultimately diminish the phosphorylation of JNK3. Furthermore, the inhibition of JNK3 phosphorylation downregulated the level of p-c-Jun and elevated neuronal cell death in the CA1 of the hippocampus. Taken together, these findings suggested that HO-1 could ameliorate brain injury by regulating the MLK3-MKK7-JNK3 signaling module, which was scaffolded by JIP1 and JNK signaling during cerebral ischemia/reperfusion.

Electroacupuncture Regulates Hippocampal Synaptic Plasticity via Inhibiting Janus-Activated Kinase 2/Signal Transducer and Activator of Transcription 3 Signaling in Cerebral Ischemic Rats.

OBJECTIVE: To determine the mechanism(s) involved in electroacupuncture (EA)-mediated improvements in synaptic plasticity in a rat model of middle cerebral artery occlusion and reperfusion (MCAO/R)-induced cognitive deficits. METHODS: Focal cerebral ischemic stroke was induced by (MCAO/R) surgery. Rats were randomly split into 4 groups: control group (sham operation control), MCAO group, Baihui (GV 20) and Shenting (GV 24) acupoint EA group (verum acupuncture, MCAO + VA), and nonacupoint EA group (control acupuncture, MCAO + CA). EA treatment was administered for 14 consecutive days in MCAO + VA and MCAO + CA groups. Neurological assessment, behavioral performance testing, and molecular biology assays were used to evaluate the MCAO/R model, EA therapeutic effect and potential therapeutic mechanism(s) of EA. RESULTS: Significant amelioration of neurological deficits was found in MCAO + VA rats compared with MCAO rats (P < .01). Moreover, learning and memory significantly improved in EA-treated rats compared with MCAO or MCAO + CA rats (P < .05) together with an increase in the number of PSD-95+ and SYN+ cells and synapses in the hippocampal CA1 region (P < .05). MCAO + VA rats also showed amelioration of pathological synaptic ultrastructural changes compared with MCAO or MCAO + CA groups (P < .001). In contrast, EA decreased the levels and phosphorylation of JAK2 (Janus-activated kinase 2) and STAT3 (signal transducer and activator of transcription 3) in the hippocampal CA1 region compared with MCAO or MCAO + CA group (P < .01). CONCLUSION: EA at GV 20 and GV 24 acupoints improved cognitive deficits in cerebral ischemic rats via the JAK2/STAT3 signaling pathway and mediated synaptic plasticity in the peri-infarct hippocampal CA1 region of rats following ischemic stroke.

Metformin Improves Neurologic Outcome Via AMP-Activated Protein Kinase-Mediated Autophagy Activation in a Rat Model of Cardiac Arrest and Resuscitation.

BACKGROUND: Sudden cardiac arrest (CA) often results in severe injury to the brain, and neuroprotection after CA has proved to be difficult to achieve. Herein, we sought to investigate the effects of metformin pretreatment on brain injury secondary to CA and cardiopulmonary resuscitation. METHODS AND RESULTS: Rats were subjected to 9-minute asphyxial CA after receiving daily metformin treatment for 2 weeks. Survival rate, neurologic deficit scores, neuronal loss, AMP-activated protein kinase (AMPK), and autophagy activation were assessed at indicated time points within the first 7 days after return of spontaneous circulation. Our results showed that metformin pretreatment elevated the 7-day survival rate from 55% to 85% and significantly reduced neurologic deficit scores. Moreover, metformin ameliorated CA-induced neuronal degeneration and glial activation in the hippocampal CA1 region, which was accompanied by augmented AMPK phosphorylation and autophagy activation in affected neuronal tissue. Inhibition of AMPK or autophagy with pharmacological inhibitors abolished metformin-afforded neuroprotection, and augmented autophagy induction by metformin treatment appeared downstream of AMPK activation. CONCLUSIONS: Taken together, our data demonstrate, for the first time, that metformin confers neuroprotection against ischemic brain injury after CA/cardiopulmonary resuscitation by augmenting AMPK-dependent autophagy activation.

Impaired Hippocampal Synaptic Plasticity and Enhanced Excitatory Transmission in a Novel Animal Model of Autism Spectrum Disorders with Telomerase Reverse Transcriptase Overexpression.

Recently, we have reported that animals with telomerase reverse transcriptase (TERT) overexpression exhibit reduced social interaction, decreased preference for novel social interaction and poor nest-building behaviors symptoms that mirror those observed in human autism spectrum disorders (ASD). Overexpression of TERT also alters the excitatory/inhibitory (E/I) ratio in the medial prefrontal cortex. However, the effects of TERT overexpression on hippocampal-dependent learning and synaptic efficacy have not been investigated. In the present study, we employed electrophysiological approaches in combination with behavioral analysis to examine hippocampal function of TERT transgenic (TERT-tg) mice and FVB controls. We found that TERT overexpression results in enhanced hippocampal excitation with no changes in inhibition and significantly impairs long-term synaptic plasticity. Interestingly, the expression levels of phosphorylated CREB and phosphory-lated CaMKIIα were significantly decreased while the expression level of CaMKIIα was slightly increased in the hippocampus of TERT-overexpressing mice. Our observations highlight the importance of TERT in normal synaptic function and behavior and provide additional information on a novel animal model of ASD associated with TERT overexpression.

Brain alpha-amylase: a novel energy regulator important in Alzheimer disease?

Reduced glucose metabolism and formation of polyglucosan bodies (PGB) are, beside amyloid beta plaques and neurofibrillary tangles, well-known pathological findings associated with Alzheimer's disease (AD). Since both glucose availability and PGB are regulated by enzymatic degradation of glycogen, we hypothesize that dysfunctional glycogen degradation is a critical event in AD progression. We therefore investigated whether alpha (α)-amylase, an enzyme known to efficiently degrade polysaccharides in the gastrointestinal tract, is expressed in the hippocampal CA1/subiculum and if the expression is altered in AD patients. Using immunohistochemical staining techniques, we show the presence of the α-amylase isotypes AMY1A and AMY2A in neuronal dendritic spines, pericytes and astrocytes. Moreover, AD patients showed reduced gene expression of α-amylase, but conversely increased protein levels of α-amylase as well as increased activity of the enzyme compared with non-demented controls. Lastly, we observed increased, albeit not significant, load of periodic acid-Schiff positive PGB in the brain of AD patients, which correlated with increased α-amylase activity. These findings show that α-amylase is expressed and active in the human brain, and suggest the enzyme to be affected, alternatively play a role, in the neurodegenerative Alzheimer's disease pathology.

Memory Retrieval Re-Activates Erk1/2 Signaling in the Same Set of CA1 Neurons Recruited During Conditioning.

The hippocampus enables a range of behaviors through its intrinsic circuits and concerted actions with other brain regions. One such important function is the retrieval of episodic memories. How hippocampal cells support retrieval of contextual fear memory remains largely unclear. Here we monitored phospho-activation of extracellular-regulated kinase (Erk1/2) across neuronal populations of the hippocampus to find that CA1 pyramidal neurons, but not cells in CA3 or dentate gyrus, specifically respond to retrieval of an aversive context. In contrast, retrieval of a neutral context that fails to elicit a threat response did not activate Erk1/2. Moreover, retrieval preferentially re-activated Erk1/2 in the same set of CA1 neurons previously activated during conditioning in a context-specific manner. By confining drug inhibition within dorsal CA1, we established the crucial role for Erk1/2 activity in retrieval of long-term memory, as well as in amygdala activation associated with fear expression. These data provide functional evidence that Erk1/2 signaling in CA1 encodes a specific neural representation of contextual memory with emotional value.

Corticosteroid-induced dendrite loss and behavioral deficiencies can be blocked by activation of Abl2/Arg kinase.

Stressor exposure induces neuronal remodeling in specific brain regions. Given the persistence of stress-related illnesses, key next steps in determining the contributions of neural structure to mental health are to identify cell types that fail to recover from stressor exposure and to identify "trigger points" and molecular underpinnings of stress-related neural degeneration. We evaluated dendrite arbor structure on hippocampal CA1 pyramidal neurons before, during, and following prolonged exposure to one key mediator of the stress response - corticosterone (cortisol in humans). Basal dendrite arbors progressively simplified during a 3-week exposure period, and failed to recover when corticosterone was withdrawn. Corticosterone exposure decreased levels of the dendrite stabilization factor Abl2/Arg nonreceptor tyrosine kinase and phosphorylation of its substrates p190RhoGAP and cortactin within 11days, suggesting that disruption of Arg-mediated signaling may trigger dendrite arbor atrophy and, potentially, behavioral abnormalities resulting from corticosterone exposure. To test this, we administered the novel, bioactive Arg kinase activator, 5-(1,3-diaryl-1H-pyrazol-4-yl)hydantoin, 5-[3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl]-2,4-imidazolidinedione (DPH), in conjunction with corticosterone. We found that repeated treatment corrected CA1 arbor structure, otherwise simplified by corticosterone. DPH also corrected corticosterone-induced errors in a hippocampal-dependent reversal learning task and anhedonic-like behavior. Thus, pharmacological compounds that target cytoskeletal regulators, rather than classical neurotransmitter systems, may interfere with stress-associated cognitive decline and mental health concerns.

Hippocampal neurophysiology is modified by a disease-associated C-terminal fragment of tau protein.

The accumulation of cleaved tau fragments in the brain is associated with several tauopathies. For this reason, we recently developed a transgenic mouse that selectively accumulates a C-Terminal 35 kDa human tau fragment (Tau35). These animals develop progressive motor and spatial memory impairment, paralleled by increased hippocampal glycogen synthase kinase 3ß activity. In this neurophysiological study, we focused on the CA1 subfield of the hippocampus, a brain area involved in memory encoding. The accumulation of Tau35 results in a significant increase of short-term facilitation of the synaptic response in the theta frequency range (10 Hz), without affecting basal synaptic transmission and long-term synaptic plasticity. Tau35 expression also alters the intrinsic excitability of CA1 pyramidal neurons. Thus, Tau35 presence is associated with increased and decreased excitability at hyperpolarized and depolarized potentials, respectively. These observations are paralleled by a hyperpolarization of the voltage-sensitivity of noninactivating K+ currents. Further investigation is needed to assess the causal link between such functional alterations and the cognitive and motor impairments previously observed in this model.