Exercise capacity and dietary restriction (DR) are linked to improved quality of life, including enhanced brain function and neuro-protection. Brain derived neurotrophic factor (BDNF) is one of the key proteins involved in the beneficial effects of exercise on brain. Low capacity runner (LCR) and high capacity runner (HCR) rats were subjected to DR in order to investigate the regulation of BDNF. HCR-DR rats out-performed other groups in a passive avoidance test. BDNF content increased significantly in the hippocampus of HCR-DR groups compared to control groups (p<0.05). The acetylation of H3 increased significantly only in the LCR-DR group. However, Chip-assay revealed that the specific binding between acetylated histone H3 and BNDF promoter was increased in both LCR-DR and HCR-DR groups. In spite of these increases in binding, at the transcriptional level only, the LCR-DR group showed an increase in BDNF mRNA content. Additionally, DR also induced the activity of cAMP response element-binding protein (CREB), while the content of SIRT1 was not altered. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) was elevated in HCR-DR groups. But, based on the levels of nuclear respiratory factor-1 and cytocrome c oxidase, it appears that DR did not cause mitochondrial biogenesis. The data suggest that DR-mediated induction of BDNF levels includes chromatin remodeling. Moreover, DR does not induce mitochondrial biogenesis in the hippocampus of LCR/HCR rats. DR results in different responses to a passive avoidance test, and BDNF regulation in LCR and HCR rats.
Brain-derived neurotrophic factor; histone; epigenetics; dietary restriction; exercise capacity
Caffeine is the most popular psychoactive drug in the world which contributes to behavioral and metabolic changes when ingested. Within the central nervous system (CNS), caffeine has a high affinity for A1 and A2a adenosine receptors. Serving as an antagonist, caffeine affects the ability for adenosine to bind to these receptors. Caffeine has been shown to alter neuronal functioning through increasing spontaneous firing. However, the effects of caffeine on non-neuronal cells in the CNS has been not been studied extensively. Microglia are one phenotype of non-neuronal glia within the CNS. Acting as phagocytes, they contribute to the immune defense system of the brain and express A1 and A2a adenosine receptors. Caffeine, therefore, may affect microglia. In order to test this hypothesis, CD-1 mice were randomly placed into one of three groups: control, low caffeine (0.3g/L water) and high caffeine (1.0g/L water) and were allowed to drink freely for 30 days. Following 30 days, brain sections were stained to reveal microglia. Morphological reconstructions and density measurements were examined in cortical and subcortical areas including the primary sensory cortex, primary motor cortex and striatum. Results indicate that microglial density throughout the brain is decreased in the caffeine groups as compared to the control. Caffeine also impacted microglia morphology shortening process length and decreasing branching. These results suggest that chronic caffeine ingestion has a systemic impact on microglia density and their activation.
Microglia; Caffeine; Adenosine
The thalamus is a critical component of the frontal cortical-basal ganglia-thalamic circuits that mediate motivation and emotional drive, planning and cognition for the development and expression of goal-directed behaviors. Each functional region of the frontal cortex is connected with specific areas of each basal ganglia (BG) structure and of the thalamus. In addition, the thalamus sends a massive, topographically organized projection directly to the striatum. Tract-tracing and physiological experiments have indicated a general topographic organization of the cortical-BG-thalamic loops and supported a model of BG function based on parallel and segregated pathways. However, the learning and execution of appropriate behavioral responses require integration of inputs related to emotional, cognitive, and motor cortical functions. Our recent data indicate that integration may occur via non-reciprocal connections between the striatum and substantia nigra and within “hot spots” of convergence between cortico-striatal projections from different functional regions. Similarly, integration may exist in the thalamus. There are non-reciprocal connections between the thalamus and cortex via thalamocortical projections that terminate in the superficial and deep cortical layers. These terminals can influence different functional cortical areas that, in turn, project to the striatum and back to the thalamus. In addition, a non-reciprocal corticothalamic projection terminates in thalamic regions that are parts of other circuits. Finally, ‘hot spots’ of convergence between terminals from different cortical regions may also occur in the thalamus as is seen in the striatum. Thus, via several different pathways, the thalamus may serve as an important center of integration of networks that underlie the ability to modulate behaviors.
There is considerable interest, from both a basic and clinical standpoint, in gaining a greater understanding of how pharmaceutical or behavioral manipulations alter fear extinction in animals. Not only does fear extinction in rodents model exposure therapy in humans, where the latter is a cornerstone of behavioral intervention for anxiety disorders such as post-traumatic stress disorder and specific phobias, but also understanding more about extinction provides basic information into learning and memory processes and their underlying circuitry. In this paper, we briefly review three principal approaches that have been used to modulate extinction processes in animals and humans: a purely pharmacological approach, the more widespread approach of combining pharmacology with behavior, and a purely behavioral approach. The pharmacological studies comprise modulation by: brain derived neurotrophic factor (BDNF), d-cycloserine, serotonergic and noradrenergic drugs, neuropeptides, endocannabinoids, glucocorticoids, histone deacetylase (HDAC) inhibitors, and others. These studies strongly suggest that extinction can be modulated by drugs, behavioral interventions, or their combination, although not always in a lasting manner. We suggest that pharmacotherapeutic manipulations provide considerable promise for promoting effective and lasting fear reduction in individuals with anxiety disorders.
d-cycloserine; fluoxetine; endocannabinoids; propranolol; yohimbine; BDNF; L-DOPA; massed extinction; context
Epinephrine, released into blood from the adrenal medulla in response to arousing experiences, is a potent enhancer of learning and memory processing. This review examines mechanisms by which epinephrine exerts its effects on these cognitive functions. Because epinephrine is largely blocked from moving from blood to brain, it is likely that the hormone's effects on memory are mediated by peripheral actions. A classic effect of epinephrine is to act at the liver to break down glycogen stores, resulting in increased blood glucose levels. The increase in blood glucose provides additional energy substrates to the brain to buttress the processes needed for an experience to be learned and remembered. In part, it appears that the increased glucose may act in the brain in a manner akin to that evident in the liver, engaging glycogenolysis in astrocytes to provide an energy substrate, in this case lactate, to augment neuronal functions. Together, the findings reveal a mechanism underlying modulation of memory that integrates the physiological functions of multiple organ systems to support brain processes.
epinephrine; glucose; astrocytes; brain metabolism and memory; vagus; memory consolidation and modulation
Work on the long-term stability of memory has identified a potentially critical role for protein kinase Mzeta (PKMζ) in maintaining established memory. PKMζ, an autonomously active isoform of PKC, is hypothesized to sustain those changes that occurred during memory formation in order to preserve the memory engram over time. Initial studies investigating the role of PKMζ were largely successful in demonstrating a role for the kinase in memory maintenance; disrupting PKMζ activity with ζ-inhibitory peptide (ZIP) was successful in disrupting a variety of established associations in a number of key brain regions. More recent work, however, has questioned both the role of PKMζ in memory maintenance and the effectiveness of ZIP as a specific inhibitor of PKMζ activity. Here, we outline the research both for and against the idea that PKMζ is a memory maintenance mechanism and discuss how these two lines of research can be reconciled. We conclude by proposing a number of studies that would help to clarify the role of PKMζ in memory and define other mechanisms the brain may use to maintain memory.
protein kinase Mzeta; PKM; ZIP; memory maintenance; epigenetics; restabilization
Long-term use of benzodiazepine-type drugs may lead to physical dependence, manifested by withdrawal syndrome after abrupt cessation of treatment. The aim of the present study was to investigate the influence of duration of treatment, as well as the role of α1-containing GABAA receptors, in development of physical dependence to diazepam, assessed through the level of anxiety and susceptibility to pentylenetetrazole (PTZ)-induced seizures, 24 h after withdrawal from protracted treatment in rats. Withdrawal of 2 mg/kg diazepam after 28, but not after 14 or 21 days of administration led to an anxiety-like behavior in the elevated plus maze. Antagonism of the diazepam effects at α1-containing GABAA receptors, achieved by daily administration of the neutral modulator βCCt (5 mg/kg), did not affect the anxiety level during withdrawal. An increased susceptibility to PTZ-induced seizures was observed during diazepam withdrawal after 21 and 28 days of treatment. Daily co-administration of βCCt further decreased the PTZ-seizure threshold after 21 days of treatment, whilst it prevented the diazepam withdrawal-elicited decrease of the PTZ threshold after 28 days of treatment. In conclusion, the current study suggests that the role of α1-containing GABAA receptors in mediating the development of physical dependence may vary based on the effect being studied and duration of protracted treatment. Moreover, the present data supports previous findings that the lack of activity at α1-containing GABAA receptors is not sufficient to eliminate physical dependence liability of ligands of the benzodiazepine type.
benzodiazepines; elevated plus maze; pentylenetetrazole test; physical dependence
Severe childhood epilepsy is commonly associated with intellectual developmental disabilities. The reasons for these cognitive deficits are likely multifactorial and will vary between epilepsy syndromes and even among children with the same syndrome. However, one factor these children have in common is the recurring seizures they experience - sometimes on a daily basis. Supporting the idea that the seizures themselves can contribute to intellectual disabilities are laboratory result demonstrating spatial learning and memory deficits in normal mice and rats that have experienced recurrent seizures in infancy. Studies reviewed here have shown that seizures in vivo and electrographic seizure activity in vitro both suppress the growth of hippocampal pyramidal cell dendrites. A simplification of dendritic arborization and resulting decrease in the number of excitatory synapses could help explain the observed cognitive disabilities. There are a wide variety of candidate mechanisms that could be involved in seizure-induced growth suppression. The challenge is designing experiments that will help focus research on a limited number of potential molecular events. Thus far results suggest that growth suppression is NMDA receptor-dependent and associated with a decrease in activation of the transcription factor CREB. The latter result is intriguing since CREB is known to play an important role in dendrite growth. Seizure-induced dendrite growth suppression may not occur as a single process in which pyramidal cells dendrites simply stop growing or grow slower compared to normal neurons. Instead, recent results suggest that after only a few hours of synchronized epileptiform in vitro dendrites appear to partially retract. This acute response is also NMDA receptor dependent and appears to be mediated by the Ca+2/calmodulin-dependent phosphatase, calcineurin. An understanding of the staging of seizure-induced growth suppression and the underlying molecular mechanisms will likely prove crucial for developing therapeutic strategies aimed at ameliorating the intellectual developmental disabilities associated with intractable childhood epilepsy.
Epilepsy; Epileptiform Activity; Hippocampus; Learning; Memory
Changes in dendritic spines structure and function play a critical role in a number of physiological processes, including synaptic transmission and plasticity, and are intimately linked to cognitive function. Alterations in dendritic spine morphogenesis occur in a number of neuropsychiatric disorders and likely underlie the cognitive and behavioral changes associated with these disorders. The neuronal guanine nucleotide exchange factor (GEF) kalirin is emerging as a key regulator of structural and functional plasticity at dendritic spines. Moreover, a series of recent studies have genetically and functionally linked kalirin signaling to several disorders, including schizophrenia and Alzheimer’s disease. Kalirin signaling may thus represent a disease mechanism and provide a novel therapeutic target.
schizophrenia; Alzheimer’s disease; mental disorder; genetic; glutamatergic; postmortem
Converging evidence indicates that processes occurring in and around neuronal dendrites are central to the pathogenesis of Alzheimer’s disease. These data support the concept of a “dendritic hypothesis” of AD, closely related to the existing synaptic hypothesis. Here we detail dendritic neuropathology in the disease and examine how Aβ, tau, and AD genetic risk factors affect dendritic structure and function. Finally, we consider potential mechanisms by which these key drivers could affect dendritic integrity and disease progression. These dendritic mechanisms serve as a framework for therapeutic target identification and for efforts to develop disease-modifying therapeutics for Alzheimer’s disease.
Ischemic preconditioning-induced neuroprotection is a well-known phenomenon. We hypothesize that this form of neuroprotection is transferable among the same type of cells. To test this hypothesis, human neuroblastoma SH-SY5Y cells were induced to become neuron-like cells. Primary rat cortical neuronal cultures were also used. These cells were subjected to various lengths of short oxygen-glucose deprivation (OGD, an in vitro simulation of ischemia) and then 1-h OGD. Some cells that were not exposed to a short episode of ischemia were incubated with culture medium from the cells that had 3- or 5-min OGD. Those cells were subjected to OGD for 1 h at 1 or 24 h after they were exposed to the medium. Cell injury was evaluated at 24 h after the 1-h OGD by lactate dehydrogenase release assay. In another experiment, cells subjected to a 3-min OGD or exposed to the medium from cells that had a 3-min OGD were harvested at 30 min after the OGD or the medium exposure for Western blotting of Akt, a prosurvival protein. Our study showed that a prior episode of ischemia lasting from 3 to 10 min significantly reduced the 1-h OGD-induced cell injury. Medium from cells subjected to a 3-min OGD also induced acute and delayed phases of neuroprotection in OGD-naïve human neuron-like cells and primary rat cortical neuronal cultures. Cells subjected to a 3-min OGD or incubated with the medium from cells exposed to a 3-min OGD had increased phosphorylated/activated Akt. The increased phosphorylated Akt and neuroprotection induced by medium transferring were inhibited by 8-cyclopentyl-1, 3-dipropylxanthine (DPCPX), an adenosine A1 receptor inhibitor. The 3-min OGD-induced neuroprotection was inhibited by LY294002, an Akt activation inhibitor. These results suggest that ischemic preconditioning-induced neuroprotection is transferable among the cells. Small molecules, such as adenosine, may mediate this effect.
adenosine A1 receptor; Akt; inter-cell preconditioning; neuroprotection
Dendritic spine abnormalities and the metabotropic glutamate receptor theory put the focus squarely on synapses and protein synthesis as the cellular locus of Fragile X syndrome. Synapses however, are only partly responsible for information processing in neuronal networks. Neurotransmitter triggered excitatory postsynaptic potentials (EPSPs) are shaped and integrated by dendritic voltage-gated ion channels. These EPSPs, and in some cases the resultant dendritic spikes, are further modified by dendritic voltage-gated ion channels as they propagate to the soma. If the resultant somatic depolarization is large enough, action potential(s) will be triggered and propagate both orthodromically down the axon, where it may trigger neurotransmitter release, and antidromically back into the dendritic tree, where it can activate and modify dendritic voltage-gated and receptor activated ion channels. Several channelopathies, both soma-dendritic (L-type calcium channels, Slack potassium channels, h-channels, A-type potassium channels) and axo-somatic (BK channels and delayed rectifier potassium channels) were identified in the fmr1-/y mouse model of Fragile X syndrome. Pathological function of these channels will strongly influence the excitability of individual neurons as well as overall network function. In this chapter we discuss the role of voltage-gated ion channels in neuronal processing and describe how identified channelopathies in models of Fragile X syndrome may play a role in dendritic pathophysiology.
voltage-gated ion channels; dendrites; integration; fmr1; FMRP
Nicotine exposure in adolescence produces lasting changes in subsequent behavioral responses to addictive agents. We gave nicotine to adolescent rats (postnatal days PN30-47), simulating plasma levels in smokers, and then examined the subsequent effects of nicotine given again in adulthood (PN90-107), focusing on cerebrocortical serotonin levels and utilization (turnover) as an index of presynaptic activity of circuits involved in emotional state. Our evaluations encompassed responses during the period of adult nicotine treatment (PN105) and withdrawal (PN110, PN120, PN130), as well as long-term changes (PN180). In males, prior exposure to nicotine in adolescence greatly augmented the increase in serotonin turnover evoked by nicotine given in adulthood, an interaction that was further exacerbated during withdrawal. The effect was sufficiently large that it led to significant depletion of serotonin stores, an effect that was not seen with nicotine given alone in either adolescence or adulthood. In females, adolescent nicotine exposure blunted or delayed the spike in serotonin turnover evoked by withdrawal from adult nicotine treatment, a totally different effect from the interaction seen in males. Combined with earlier work showing persistent dysregulation of serotonin receptor expression and receptor coupling, the present results indicate that adolescent nicotine exposure reprograms future responses of 5HT systems to nicotine, changes that may contribute to life-long vulnerability to relapse and re-addiction.
Adolescence; Nicotine; Serotonin; Sex differences; Withdrawal
Zinc is an allosteric modulator of glycine receptor function, enhancing the effects of glycine at nM to low μM concentrations, and inhibiting its effects at higher concentrations. Because of zinc’s high potency at the glycine receptor, there exists a possibility that effects attributed solely to exogenously-applied glycine in fact contain an undetected contribution of zinc acting as an allosteric modulator. We found that glycine solutions made up in standard buffers and using deionized distilled water produced effects that could be decreased by the zinc chelator tricine. This phenomenon was observed in three different vials tested and persisted even if vials were extensively washed, suggesting the zinc was probably present in the buffer constituents. In addition, polystyrene, but not glass, pipets bore a contaminant that enhanced glycine receptor function and that could also be antagonized by tricine. Our findings suggest that without checking for this effect using a chelator such as tricine, one cannot assume that responses elicited by glycine applied alone are not necessarily also partially due to some level of allosteric modulation by zinc.
Zinc; Tricine; Allosteric modulation; Glycine receptor; electrophysiology; Xenopus oocytes
This study explores how glucocorticoids sensitize the developing brain to the organophosphate pesticide, chlorpyrifos. Pregnant rats received a standard therapeutic dose (0.2 mg/kg) of dexamethasone on gestational days 17–19; pups were given subtoxic doses of chlorpyrifos on postnatal days 1–4, (1 mg/kg, <10% cholinesterase inhibition). We evaluated serotonin (5HT) synaptic function from postnatal day 30 to day 150, assessing the expression of 5HT receptors and the 5HT transporter, along with 5HT turnover (index of presynaptic impulse activity) in brain regions encompassing all the 5HT projections and cell bodies. These parameters are known targets for neurodevelopmental effects of dexamethasone and chlorpyrifos individually. In males, chlorpyrifos evoked overall elevations in the expression of 5HT synaptic proteins, with a progressive increase from adolescence to adulthood; this effect was attenuated by prenatal dexamethasone treatment. The chlorpyrifos-induced upregulation was preceded by deficits in 5HT turnover, indicating that the receptor upregulation was an adaptive response to deficient presynaptic activity. Turnover deficiencies were magnified by dexamethasone pretreatment, worsening the functional impairment caused by chlorpyrifos. In females, chlorpyrifos-induced receptor changes reflected relative sparing of adverse effects compared to males. Nevertheless, prenatal dexamethasone still worsened the 5HT turnover deficits and reduced 5HT receptor expression in females, demonstrating the same adverse interaction. Glucocorticoids are used in 10% of U.S. pregnancies, and are also elevated in maternal stress; accordingly, our results indicate that this group represents a large subpopulation that may have heightened vulnerability to developmental neurotoxicants such as the organophosphates.
Chlorpyrifos; Dexamethasone; Glucocorticoids; Organophosphate pesticides; Preterm delivery; Serotonin
Vascular early response gene (Verge) is a novel immediate early gene that is highly expressed during developmental angiogenesis and after ischemic insults in adult brain. However, the role of Verge after neonatal injury is not known. In the present study, we investigated the hypothesis that Verge contributes to vascular remodeling and tissue repair after neonatal ischemic injury. The Rice–Vanucci model (RVM) was employed to induce neonatal stroke in both Verge knockout (KO) and wild-type (WT) postnatal day 10 (P10) mice. Histological and behavioral outcomes at acute (24 h), subacute (7 days) and chronic (30 days) phases were evaluated. Angiogenesis, neurogenesis, and glial scar formation were also examined in the ischemic brain. No significant differences in outcomes were found between WT and Verge mice at 24 h or 7 days after stroke. However genetic deletion of Verge led to pronounced cystic cavitation, decreased angiogenensis and glial scar formation in the ischemic hemisphere compared to WT mice at 30 days. Verge KO mice also had significantly worse functional outcomes at 30 days which was accompanied by decreased neurogenesis and angiogenesis in the ischemic hemisphere. Our study suggests that Verge plays an important role in the induction of neurogenesis and angiogenesis after ischemia, contributes to improved tissue repair, and enhances chronic functional recovery.
Angiogenesis; Ischemic stroke; Neonate; Neurogenesis; Vascular early response gene
We aimed to evaluate the novel high-affinity and relatively lipophilic CB1 receptor (CB1R) antagonist radioligand [125I]SD7015 for SPECT imaging of CB1Rs in vivo using the multiplexed multipinhole dedicated small animal SPECT/CT system, NanoSPECT/CTPLUS (Mediso, Budapest, Hungary), in knock-out CB1 receptor knock-out (CB1R-/-) and wildtype mice. In order to exclude possible differences in cerebral blood flow between the two types of animals, HMPAO SPECT scans were performed, whereas in order to confirm the brain uptake differences of the radioligand between knock-out mice and wildtype mice, in vivo scans were complemented with ex vivo autoradiographic measurements using the brains of the same animals. With SPECT/CT imaging, we measured the brain uptake of radioactivity, using %SUV (% standardised uptake values) in CB1R-/- mice (n = 3) and C57BL6 wildtype mice (n = 7) under urethane anaesthesia after injecting [125I]SD7015 intravenously or intraperitoneally. The Brookhaven Laboratory mouse MRI atlas was fused to the SPECT/CT images by using a combination of rigid and non-rigid algorithms in the Mediso Fusion™ (Mediso, Budapest, Hungary) and VivoQuant (inviCRO, Boston, MA, USA) softwares. Phosphor imager plate autoradiography (ARG) was performed on 4 μm-thin cryostat sections of the excised brains. %SUV was 8.6 ± 3.6 (average ± SD) in CB1R-/- mice and 22.1 ± 12.4 in wildtype mice between 2 and 4 h after injection (p < 0.05). ARG of identically taken sections from wildtype mouse brain showed moderate radioactivity uptake when compared with the in vivo images, with a clear difference between grey matter and white matter, whereas ARG in CB1R(-/-) mice showed practically no radioactivity uptake. [125I]SD7015 enters the mouse brain in sufficient amount to enable SPECT imaging. Brain radioactivity distribution largely coincides with that of the known CB1R expression pattern in rodent brain. We conclude that [125I]SD7015 should be a useful SPECT radioligand for studying brain CB1R in mouse and rat disease models.
Endocannabinoid CB1 receptor (CB1R); Single photon emission computed tomography (SPECT); Molecular imaging biomarker; [125I]SD7015; Knock-out CB1R-/- mouse; Multiplexed multipinhole dedicated small animal SPECT/CT system
Cannabinoid type-1 receptors (CB1Rs) modulate synaptic neurotransmission by participating in retrograde signaling in the adult brain. Increasing evidence suggests that cannabinoids through CB1Rs play an important role in the regulation of motor activities in the striatum. In the present study, we used human brain samples to examine the relationship between CB1R and dopamine receptor density in case of Parkinson’s disease (PD).
Post mortem putamen, nucleus caudatus and medial frontal gyrus samples obtained from PD patients were used for CB1R and dopamine D2/D3 receptor autoradiography. [125I]SD7015, a novel selective CB1R inverse agonist, developed by a number of the present co-authors, and [3H]raclopride, a dopamine D2/D3 antagonist, were used as radioligands. Our results demonstrate unchanged CB1R density in the putamen and nucleus caudatus of deceased PD patients, treated with levodopa (l-DOPA). At the same time dopamine D2/D3 receptors displayed significantly decreased density levels in case of PD putamen (control: 47.97 ± 10.00 fmol/g, PD: 3.73 ± 0.07 fmol/g (mean ± SEM), p < 0.05) and nucleus caudatus (control: 30.26 ± 2.48 fmol/g, PD: 12.84 ± 5.49 fmol/g, p < 0.0005) samples. In contrast to the putamen and the nucleus caudatus, in the medial frontal gyrus neither receptor densities were affected.
Our data suggest the presence of an unaltered CB1R population even in late stages of levodopa treated PD. This further supports the presence of an intact CB1R population which, in line with the conclusion of earlier publications, may be utilized as a pharmacological target in the treatment of PD. Furthermore we found discrepancy between a maintained CB1R population and a decreased dopamine D2/D3 receptor population in PD striatum. The precise explanation of this conundrum requires further studies with simultaneous examination of the central cannabinoid and dopaminergic systems in PD using higher sample size.
Parkinson’s disease; Endocannabinoid CB1 receptor; Dopamine D2/D3 receptor; Molecular imaging biomarker; Human brain autoradiography; Striatum
A pre-exposure to isoflurane reduces ischemic brain injury in rodents (isoflurane preconditioning). This neuroprotection has acute and delayed phases. Our previous in vitro studies suggest that the acute phase may involve excitatory amino acid transporters (EAAT). We determine whether this protection involves EAAT3, the major neuronal EAAT. Adult male EAAT3 knockout mice and their wild-type littermates were exposed or were not exposed to 1.5% isoflurane for 30 min. Sixty minutes later, they were subjected to a 90- or 60-min middle cerebral arterial occlusion (MCAO). Their neurological outcomes were evaluated 24 h after the MCAO. In another experiment, cerebral cortex was harvested for Western blotting at 30 min after animals were exposed to 1.5% isoflurane for 30 min. Here, we showed that isoflurane reduced brain infarct volumes and improved neurological functions of wild-type mice after a 90-min MCAO. However, isoflurane pre-exposure did not change the neurological outcome of EAAT3 knockout mice no matter whether the MCAO was for 90 min or 60 min. Isoflurane increased phospho-Akt, a survival-promoting protein, in the wild-type mice but not in the EAAT3 knockout mice. The isoflurane-induced neuroprotection in the wild-type mice was abolished by LY294004, an Akt activation inhibitor. LY294004 alone did not affect the neurological outcome of the wild-type or EAAT3 knockout mice after focal brain ischemia. These results suggest that the isoflurane preconditioning-induced acute phase of neuroprotection involves EAAT3. The downstream event includes Akt activation.
Akt; glutamate transporter; isoflurane; neuroprotection; preconditioning
The availability of mutant mice that lack either MAO A or MAO B has created unique profiles in the central and peripheral availability of serotonin, norepinephrine, dopamine, and phenylethylamine. This paper summarizes some of the current known phenotypic findings in MAO A knock-out mice and contrast these with those of MAO B knock-out mice. Differences are discussed in relation to the biochemical, behavioral, and physiologic changes investigated to date, as well as the role played by redundancy mechanisms, adaptational responses, and alterations in neurodevelopment.
Monoamine oxidase; Serotonin; Norepinephrine; Phenylethylamine; Dopamine
Exposure to repeated stress is often associated with psychopathology. However, our understanding of the underlying neural circuitry that regulates responses to repeated stress is limited. The posterior paraventricular thalamus (pPVT) is a brain region responsible for transmission of multimodal sensory information to limbic structures that regulate responses to both acute and repeated stress. Orexin-containing cells originating in the hypothalamus heavily innervate the pPVT. Our previous work has shown that activation of orexin1 receptors in the pPVT during repeated swim stress is important for facilitation of the hypothalamic-pituitary-adrenal (HPA) axis response to subsequent novel restraint. However, the genes responsible for these orexin-mediated adaptations to repeated stress are not known. Using a custom PCR array we examined the expression of 186 specific mRNAs in the pPVT of animals exposed to repeated swim stress (4 days of 15 min swim/day) with or without direct pPVT microinfusion of the orexin1 receptor antagonist SB334867 prior to each daily swim stress. Tissue was collected the next morning under basal non stressed conditions. Repeated stress and/or orexin receptor blockade significantly altered expression of only 9 specific genes including growth factors (Vegfa, Bax and Mt3), G-protein coupled receptors (Adora2a, Grm2 and Crhr1), immune-related genes (Ptgs2 and Cx3cr1) and an epigenetic-related gene (Hdac5). These genes represent potential targets for further characterization of orexin-mediated adaptations to repeated stress in the pPVT.
Hypocretin; Hypothalamic pituitary adrenal; PCR array; Crhr1; Vegfa; Bax; Mt3; Ptgs2; Ador2a; Grm2; Cx3cr1; Hdac5
We investigated the plasticity effects of diabetes mellitus and diuresis on the non-adrenergic non-cholinergic (NANC) and purinergic (P2X-type) contractile responses in longitudinal rat bladder strips. Female Sprague-Dawley rats received streptozotocin to induce diabetes, or sucrose in water to induce diuresis as a control condition for polyuria. Experiments were carried out at four weeks after treatments, using bladders from not-treated rats as control. Urinary bladder strips were electrically stimulated throughout the experiments to generate neurally evoked contractions (NEC). In all cases, P2X-mediated purinergic contractions were evaluated at the beginning and end of the stimulations with α,β-Methylene Adenosine Triphosphate (α,βMeATP). The NANC responses were assessed by using two independent protocols. First, cholinergic receptors were activated with carbachol (CCh), followed by inhibition of the muscarinic component with atropine. In the second protocol, the application order for CCh and atropine was reversed. The NANC response, unmasked with the application of atropine, and the P2X purinergic contractions were analyzed. NANC contractions in diabetic bladder strips are more resistant to the desensitizing effects caused by activation of cholinergic receptors. In early stages of experimental diabetes, NANC responses in diabetic strips are less sensitive to functional inhibition mediated by the cholinergic activation. However, P2X-mediated purinergic contractions are more sensitive to desensitization in diabetic or diuretic bladders. For instance preventing muscarinic receptor activation with atropine does not counteract the desensitization of purinergic contractions in either diabetic or diuretic strips. We suggest that diabetes may induce a plasticity of the NANC and P2X-mediated bladder contractile responses. The first one may be associated with diabetic neuropathic damage to bladder nerves, while impaired P2X purinergic contractions might be associated with detrusor hypertrophy observed in diabetic and diuretic strips.
Diabetic bladder dysfunction; purinergic receptor; cholinergic receptor; non-adrenergic non-cholinergic response; neurally evoked contraction; detrusor muscle
•Newly developed methods allow manipulation of hippocampus-dependent memories.•Cued reactivation during sleep and transcranial stimulation can enhance memories.•Pharmacological agents can delete memories.•Optogenetics and DREADDs can be used to incept memories.•Electrophysiology and fMRI have been used to investigate the underlying mechanisms.
Here we provide a brief overview of recent research on memory manipulation. We focus primarily on memories for which the hippocampus is thought to be required due to its central importance in the study of memory. The repertoire of methods employed is expanding and includes optogenetics, transcranial stimulation, deep brain stimulation, cued reactivation during sleep and the use of pharmacological agents. In addition, the possible mechanisms underlying these memory changes have been investigated using techniques such as single unit recording and functional magnetic resonance imaging (fMRI).
This article is part of a Special Issue entitled ‘Memory enhancement’.
Memory consolidation; Sleep; Hippocampus; Fear conditioning; Extinction; Reconsolidation