Defense reaction elicited by microinjection of kainic acid into the medial hypothalamus of the rat: antagonism by a GABAA receptor agonist.

Electrical stimulation of either the midbrain central gray or the medial hypothalamus induces a defense reaction in the rat, characterized mainly by increased locomotion, rearing, and leaping. However, microinjection of the excitatory amino acid glutamate was effective only in the former region. Because excitatory amino acids do not depolarize axons of passage, it was suggested that the hypothalamus is devoid of soma/dendrites of neurons commanding the defense reaction. In the present study, we show that a subtoxic dose (60 pmol) of another excitatory amino acid, kainic acid, injected into the medial hypothalamus significantly enhanced locomotion and rearing of Wistar rats systematically observed in an open field. Similar behavioral changes have been reported following microinjection of drugs impairing GABAergic neurotransmission. Local pretreatment with the GABAA receptor agonist THIP (2 nmol) blocked the effect of kainic acid. Therefore, the medial hypothalamus of the rat seems to contain a population of neuronal cell bodies commanding the defense reaction, which is activated by excitatory amino acids and tonically inhibited by GABAergic fibers.     

Glutamate-hypothalamic-pituitary-adrenal axis interactions: implications for mood and anxiety disorders

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is a pathologic feature of certain mood and anxiety disorders that results in the increased production and secretion of corticotropin-releasing factor. There is increasing preclinical evidence that glutamate, an excitatory amino acid, plays an important role in the regulation of the HPA axis. Activation of glutamatergic projections to limbic structures such as the amygdala and brainstem structures such as the nucleus tractus solitarius is implicated in the stress response. There are laboratory and clinical suggestions that glutamatergic N-methyl-D-aspartate (NMDA) receptor antagonists function as antidepressants, and that chronic antidepressant treatments have a significant impact on NMDA receptor function. Clinical investigations of glutamate antagonists in patients with mood and anxiety disorders are in their infancy, with a few reports suggesting the presence of mood-elevating properties. Ultimately, HPA axis modulators, serotonin-enhancing agents, and glutamate antagonists might serve to increase neurotropic factors in key brain regions for affective and anxiety regulation, providing a putative final common pathway.     

Desensitization of postsynaptic glutamate receptors contributes to high-frequency homosynaptic depression of aplysia sensorimotor connections

Withdrawal reflexes of Aplysia are mediated in part by a monosynaptic circuit of sensory (SN) and motor (MN) neurons. A brief high-frequency burst of spikes in the SN produces excitatory postsynaptic potentials (EPSPs) that rapidly decrease in amplitude during the burst of activity. It is generally believed that this and other (i.e., low-frequency) forms of homosynaptic depression are entirely caused by presynaptic mechanisms (e.g., depletion of releasable transmitter). The present study examines the contribution that desensitization of postsynaptic glutamate receptors makes to homosynaptic depression. Bath application of cyclothiazide, an agent that reduces desensitization of non-NMDA glutamate receptors, reduced high-, but not low-frequency synaptic depression. Thus, a postsynaptic mechanism, desensitization of glutamate receptors, can also contribute to homosynaptic depression of sensorimotor synapses.     

Stressor controllability and learned helplessness research in the United States: Sensitization and fatigue processes

Recent work in the learned helplessness paradigm suggests that neuronal sensitization and fatigue processes are critical to producing the behavioral impairment that follows prolonged exposure to an unsignaled inescapable stressor such as a series of electric tail shocks. Here we discuss how an interaction between serotonin (5-HT) and corticosterone (CORT) sensitizes GABA neurons early in the pretreatment session with inescapable shock. We propose that this process eventually depletes GABA, thus removing an important form of inhibition on excitatory glutamate transmission in the amygdala, hippocampus, and frontal cortex. When rats are re-exposed to shock during shuttle-escape testing 24 hrs later, the loss of inhibition (as well as other excitatory effects) results in unregulated excitation of glutamate neurons. This state of neuronal over-excitation rapidly compromises metabolic homeostasis. Metabolic fatigue results in compensatory inhibition by the nucleoside adenosine, which regulates neuronal excitation with respect to energy availability. The exceptionally potent form of inhibition associated with adenosine receptor activation yields important neuroprotective benefits under conditions of metabolic failure, but also precludes the processing of information in fatigued neurons. The substrates of adaptive behavior are removed; performance deficits ensue.     

Stressor Controllability and Learned Helplessness Research in the United States: Sensitization and Fatigue Processes

Recent work in the learned helplessness paradigm suggests that neuronal sensitization and fatigue processes are critical to producing the behavioral impairment that follows prolonged exposure to an unsignaled inescapable stressor such as a series of electric tail shocks. Here we discuss how an interaction between serotonin (5-HT) and corticosterone (CORT) sensitizes GABA neurons early in the pretreatment session with inescapable shock. We propose that this process eventually depletes GABA, thus removing an important form of inhibition on excitatory glutamate transmission in the amygdala, hippocampus, and frontal cortex. When rats are re-exposed to shock during shuttle-escape testing 24 hrs later, the loss of inhibition (as well as other excitatory effects) results in unregulated excitation of glutamate neurons. This state of neuronal over-excitation rapidly compromises metabolic homeostasis. Metabolic fatigue results in compensatory inhibition by the nucleoside adenosine, which regulates neuronal excitation with respect to energy availability. The exceptionally potent form of inhibition associated with adenosine receptor activation yields important neuroprotective benefits under conditions of metabolic failure, but also precludes the processing of information in fatigued neurons. The substrates of adaptive behavior are removed; performance deficits ensue.     

Cellular and molecular mechanisms underlying learning and memory impairments produced by cannabinoids

Why does smoking marijuana impair learning and memory? Behavioral studies suggest that a disruption of normal hippocampal function contributes to these deficits. In vitro experiments find that cannabinoid receptor activation reduces neurotransmitter release below the levels required to trigger long-term changes in synaptic strength in the hippocampus. Cannabinoids reduce glutamate release through a G-protein-mediated inhibition of the calcium channels responsible for neurotransmitter release from hippocampal neurons. These mechanisms likely play a role in the learning and memory impairments produced by cannabinoids and by endogenous cannabinoid receptor ligands.     

Cellular abnormalities and synaptic plasticity in seizure disorders of the immature nervous system

The nervous system has an enhanced capacity to generate seizures during a restricted phase of postnatal development. Studies in animals and particularly in in vitro brain slices from hippocampus and neocortex have been instrumental in furthering an understanding of the underlying processes. Developmental alterations in glutaminergic excitatory synaptic transmission appear to play a key role in the enhanced seizure susceptible of rodents during the second and third week of life. Prior to this period, the number of excitatory synapses is relatively low. The scarcity of connections and the inability of the existing synapses to release glutamate when activated at high frequencies likely contribute importantly to the resistance of neonates to seizures. However, at the beginning of week 2, a dramatic outgrowth of excitatory synapses occurs, and these synapses are able to faithfully follow activation at high frequencies. These changes, coupled with the prolonged nature of synaptic potentials in early life, likely contribute to the ease of seizure generation. After this time, seizure susceptibility declines, patterns of local synaptic connectivity remodel, and some synapses are pruned. Concurrently, the duration of excitatory postsynaptic potentials shortens due at least in part to a switch in the subunit composition of postsynaptic receptors. Other studies have examined the mechanisms underlying chronic epilepsy initiated in early life. Models of both cortical dysplasia and recurrent early-life seizures suggest that alterations in the normal development of excitatory synaptic transmission can contribute importantly to chronic epileptic conditions. In the recurrent early-life seizure model, abnormal use-dependent selection of subpopulations of excitatory synapses may play a role. In experimental cortical dysplasia, alterations in the molecular composition of postsynaptic receptor are observed that favor subunit combinations characteristic of infancy.     

Cognitive disruption and altered hippocampus synaptic function in Reelin haploinsufficient mice

The heterozygote reeler mouse (HRM) shows many neuroanatomical and biochemical features that are also present in some human cognitive disorders, such as schizophrenia. In the present study, hippocampal dependent plasticity and cognitive function of the HRM were characterized in detail in an attempt to reveal phenotypic functional differences that result from Reelin haploinsufficiency. The HRM and wild type mice show similar levels of overall activity, coordination, thermal nociception, startle responses, and anxiety-like behavior. In addition, both genotypes show similar shock threshold, identical cued freezing behavior and comparable spatial learning in Morris water maze tasks. However, a significant reduction in contextual fear conditioned learning was observed in the HRM. Electrophysiological studies in hippocampal CA1 synapses revealed a plethora of differences between genotypes. The HRM exhibits reduced field excitatory postsynaptic potentials in responses to similar synaptic inputs, lowered paired pulse facilitation ratio and impaired long-term depression and tetanus-induced long-term potentiation (LTP). Also, deficits were detected in LTP elicited by theta burst stimulation or by a whole cell pairing protocol. These physiologic differences could not be accounted for by changes in the overall amount of glutamate receptor subunits. In addition, it was determined that network-driven excitatory and inhibitory activities recorded in CA1 pyramidal neurons showed that the HRM had comparable amplitude and frequency of spontaneous excitatory postsynaptic currents, but a marked reduction in spontaneous inhibitory postsynaptic currents. Thus, the HRM exhibits a specific hippocampal-dependent learning deficit accompanied with a pronounced impairment of hippocampal plasticity and functional inhibitory innervation.     

The role of inhibition in a spreading-activation model of language production. I. The psycholinguistic perspective

Spreading-activation models of language production are only workable to the extent that they manage to solve the heat death problem, i.e., the danger that too many nodes in the network are overactive at the same time. Therefore, a delicate balance between activational and deactivational forces has to be struck. Of the three prevailing dampening mechanisms of decay, self-inhibition and other-inhibition, the latter has been selected for closer scrutiny. The key proposal of this two-part article is that activation-based models of language production cannot afford to do without an inhibitory component, in particular lateral inhibition among nodes of the same level. Psycholinguistic evidence is reviewed in an attempt to insulate inhibitory from excitatory mechanisms. Although it is difficult in normal adult language use to distinguish between the effects of excessive activation and insufficient inhibition, some patterns from language acquisition and aphasia can be shown to follow from inhibitory rather than excitatory problems, thus demonstrating the reality of inhibition. In a system of activational and deactivational forces, other-inhibition is claimed to have the excitatory mechanism of syntax as its natural opponent. It is finally argued that other-inhibition offers an explanation for some puzzling findings from the experimental literature.     

Evolution,depression and counselling

In this paper a framework of evolutionary psychology is used to develop a model of depression. In this model depression is seen as not normally a biochemical illness or disorder, but instead as usually due to the person becoming trapped within a psychologically activated but unwanted and inappropriate suite of natural emotions, with the activation coming from a perception of a major decline in personal usefulness that can include failure, guilt, shame or perceived rejection. A neuropsychological observation that supports this model is described. The implications of the model for counselling with depressed clients are outlined in terms of a multi-dimensional approach, oriented around perceived usefulness. It is predicted that clients receiving such counselling will recover more rapidly and be less likely to suffer a relapse than those receiving just drugs or a form of counselling that covers fewer dimensions.     

Modern aspects of epilepsy research and its application

At present most authors agree with the hypothesis that epilepsy is primarily caused by an imbalance of inhibitory and excitatory transmitter systems of CNS in favour of the latter. Epilepsy research focuses more and more on disorders in structures using amino acids as transmitters. There is a world-wide searching for new antiepileptic strategies with an emphasis on a causally guided therapy. Besides possibilities of pharmacological enhancement of GABA-mediated inhibition, e.g. by recently tested GABA prodrugs, highly potent antagonists of transmitter glutamate, acting as anticonvulsant drugs, are expected to gain in significance for clinical practice.     

Memantine ameliorates scopolamine-induced amnesia in chicks trained on taste-avoidance learning

In day-old chicks trained on the one-trial taste-avoidance task, activation of NMDA receptors by glutamate is particularly important in the initial stages of memory consolidation. In addition, acetylcholine receptor activation has been shown to be a necessary component of memory formation for this task because injection of scopolamine produces amnesia. Memantine, a non-competitive NMDA receptor antagonist, improves memory formation under certain impairing circumstances, despite inhibiting the activation of NMDA receptors. The present experiments tested the hypothesis that memantine can ameliorate scopolamine-induced amnesia in day-old chicks (Gallus gallus domesticus) trained on the one-trial taste-avoidance task. Three experiments assessed the effects of scopolamine, memantine, and glutamate in this task. The results of Experiment 1 demonstrated that 50.0 mM scopolamine produces significant amnesia. In Experiment 2, 1.0 mM memantine reversed the scopolamine-induced amnesia, while other doses were ineffective. In Experiment 3, injection of 50.0 mM glutamate in combination with scopolamine reversed the memantine amelioration. These results indicate a relationship between glutamate and acetylcholine in memory formation in the day-old chick.     

Burnout and risk of cardiovascular disease: evidence, possible causal paths, and promising research directions

Burnout is characterized by emotional exhaustion, physical fatigue, and cognitive weariness, resulting from prolonged exposure to work-related stress. The authors review the accumulated evidence suggesting that burnout and the related concept of vital exhaustion are associated with increased risk of cardiovascular disease and cardiovascular-related events. The authors present evidence supporting several potential mechanisms linking burnout with ill health, including the metabolic syndrome, dysregulation of the hypothalamic-pituitary-adrenal axis along with sympathetic nervous system activation, sleep disturbances, systemic inflammation, impaired immunity functions, blood coagulation and fibrinolysis, and poor health behaviors. The association of burnout and vital exhaustion with these disease mediators suggests that their impact on health may be more extensive than currently indicated.     

Central synaptic mechanisms underlie short-term olfactory habituation in Drosophila larvae

Naive Drosophila larvae show vigorous chemotaxis toward many odorants including ethyl acetate (EA). Chemotaxis toward EA is substantially reduced after a 5-min pre-exposure to the odorant and recovers with a half-time of ～20 min. An analogous behavioral decrement can be induced without odorant-receptor activation through channelrhodopsin-based, direct photoexcitation of odorant sensory neurons (OSNs). The neural mechanism of short-term habituation (STH) requires the (1) rutabaga adenylate cyclase; (2) transmitter release from predominantly GABAergic local interneurons (LNs); (3) GABA-A receptor function in projection neurons (PNs) that receive excitatory inputs from OSNs; and (4) NMDA-receptor function in PNs. These features of STH cannot be explained by simple sensory adaptation and, instead, point to plasticity of olfactory synapses in the antennal lobe as the underlying mechanism. Our observations suggest a model in which NMDAR-dependent depression of the OSN-PN synapse and/or NMDAR-dependent facilitation of inhibitory transmission from LNs to PNs contributes substantially to short-term habituation.     

Mediation analyses of Internet-facilitated cognitive behavioral intervention for maternal depression

This study evaluated the putative mediating mechanisms of an Internet-facilitated cognitive-behavioral therapy (CBT) intervention for depression tailored to economically disadvantaged mothers of preschool-age children. The CBT mediators were tested across two previously published randomized controlled trials which included the same measures of behavioral activation, negative thinking, and savoring of positive events. Trial 1 included 70 mothers with elevated depressive symptoms who were randomized to either the eight-session, Internet-facilitated intervention (Mom-Net) or to treatment as usual. Trial 2 included 266 mothers with elevated depressive symptoms who were randomized to either Mom-Net or to a motivational interviewing and referral to services condition. Simple mediation models tested each putative mediator independently followed by tests of multiple mediation that simultaneously included all three mediators in the model to assess the salient contributions of each mediator. The pattern of results for the mediating effects were systematically replicated across the two trials and suggest that behavioral activation and negative thinking are salient mediators of the Mom-Net intervention; significant mediating effects for savoring were obtained only in the simple mediation models and were not obtained in the multiple mediation models.     

从进化观点看应激对健康的影响

从进化的观点解释了不同生物体应对应激的不同行为策略及其生理基础,和由此引起的对不同应激性疾病易感性的差异。行为策略和生理基础的差异使得一定环境条件下引发的应激反应对不同个体产生了不同的非稳态获益和代价（非稳态负荷)。非稳态的获益和代价影响了健康和疾病间的平衡：攻击性个体由于非稳态调质失调,更可能出现冲动控制障碍、高血压、自身免疫性疾病、慢性疲劳状态等;反之,非攻击性个体由于非稳调质过度释放,更易发生焦虑障碍、抑郁症、代谢综合症等     

Glycine(B) receptor antagonists and partial agonists prevent memory deficits in inhibitory avoidance learning

Activation of N-methyl-d-aspartate (NMDA) receptors has been hypothesized to mediate certain forms of learning and memory. This hypothesis is based on the ability of competitive and uncompetitive NMDA receptor antagonists to disrupt learning. We investigated the effects of glycine site antagonists and partial agonists on deficits of acquisition (learning) and consolidation (memory) in a single trial inhibitory avoidance learning paradigm. Posttraining administration of either hypoxia (exposure to 7% oxygen) or the convulsant drug pentylenetetrazole (PTZ) (45 mg/kg) to mice impaired consolidation without producing neuronal cell death. Pretreatment with the competitive glycine antagonist 7-chlorokynurenic acid (7KYN) and the glycine partial agonists 1-aminocyclopropanecarboxylic acid (ACPC) and (+)HA-966 prevented memory deficits induced by hypoxia and PTZ, but did not affect scopolamine-induced learning impairment. In addition, ACPC prevented consolidation deficits evoked by a nonexcitotoxic concentration of l-trans-pyrrolidine-2, 4-dicarboxylate, a competitive inhibitor of glutamate transport that increases extracellular levels of glutamate. Moreover, (+)HA-966, 7KYN, and ACPC facilitated both acquisition and consolidation of inhibitory avoidance training, an effect that was dose-dependent and reversed by glycine. These results indicate that memory deficits induced by both hypoxia and PTZ involve NMDA receptor activation. Furthermore, the present findings demonstrate that glycine site antagonists and partial agonists prevent memory deficits of inhibitory avoidance learning by affecting consolidation, but not acquisition processes.     

Associative, bidirectional changes in neural signaling utilizing NMDA receptor- and endocannabinoid-dependent mechanisms

Persistent, bidirectional changes in synaptic signaling (that is, potentiation and depression of the synapse) can be induced by the precise timing of individual pre- and postsynaptic action potentials. However, far less attention has been paid to the ability of paired trains of action potentials to elicit persistent potentiation or depression. We examined plasticity following the pairing of spike trains in the touch mechanosensory neuron (T cell) and S interneuron (S cell) in the medicinal leech. Long-term potentiation (LTP) of T to S signaling was elicited when the T-cell spike train preceded the S-cell train. An interval 0 to +1 sec between the T- and S-cell spike trains was required to elicit long-term potentiation (LTP), and this potentiation was NMDA receptor (NMDAR)-dependent. Long-term depression (LTD) was elicited when S-cell activity preceded T-cell activity and the interval between the two spike trains was -0.2 sec to -10 sec. This surprisingly broad temporal window involved two distinct cellular mechanisms; an NMDAR-mediated LTD (NMDAR-LTD) when the pairing interval was relatively brief (<-1 sec) and an endocannabinoid-mediated LTD (eCB-LTD) when longer pairing intervals were used (-1 to -10 sec). This eCB-LTD also required activation of a presynaptic transient receptor potential vanilloid (TRPV)-like receptor, presynaptic Ca(2+) release from intracellular stores and activation of voltage-gated Ca(2+) channels (VGCCs). These findings demonstrate that the pairing of spike trains elicits timing-dependent forms of LTP and LTD that are supported by a complex set of cellular mechanisms involving NMDARs and endocannabinoid activation of TRPV-like receptors.     

GABA, glutamate, dopamine and serotonin transporters expression on memory formation and amnesia

Notwithstanding several neurotransmission systems are frequently related to memory formation, amnesia and/or therapeutic targets for memory alterations, the role of transporters γ-aminobutyric acid (GABA, GAT1), glutamate (neuronal glutamate transporter excitatory amino acid carrier; EACC1), dopamine (DAT) and serotonin (SERT) is poorly understood. Hence, in this paper Western-blot analysis was used to evaluate expression changes on them during memory formation in trained and untrained rats treated with the selective serotonin transporter inhibitor fluoxetine, the amnesic drug d-methamphetamine (METH) and fluoxetine plus METH. Transporters expression was evaluated in the hippocampus, prefrontal cortex and striatum. Data indicated that in addition of memory performance other behavioral parameters (e.g., explorative behavior, food-intake, etc.) that memory formation was recorded. Thus, memory formation in a Pavlovian/instrumental autoshaping was associated to up-regulation of prefrontal cortex GAT1 and EAAC1, striatal SERT, DAT and EACC1; while, hippocampal EACC1, GAT1 and SERT were down-regulated. METH impaired short (STM) and long-term memory (LTM), at 24 or 48h. The METH-induced amnesia down-regulated SERT, DAT, EACC1 and GAT1 in hippocampus and the GAT1 in striatum; no-changes were observed in prefrontal cortex. Post-training administration of fluoxetine improved LTM (48h), which was associated to DAT, GAT1 (prefrontal cortex) up-regulation, but GAT1 (striatum) and SERT (hippocampus) down-regulation. Fluoxetine plus METH administration was able to prevent amnesia, which was associated to DAT, EACC1 and GAT1 (prefrontal cortex), SERT and DAT (hippocampus) and EACC1 or DAT (striatal) up-regulation. Together these data show that memory formation, amnesia and anti-amnesic effects are associated to specific patters of transporters expression.     

Age-dependent glutamate induction of synaptic plasticity in cultured hippocampal neurons

A common denominator for the induction of morphological and functional plasticity in cultured hippocampal neurons involves the activation of excitatory synapses. We now demonstrate massive morphological plasticity in mature cultured hippocampal neurons caused by a brief exposure to glutamate. This plasticity involves a slow, 70%-80% increase in spine cross-section area associated with a significant reduction in the width of dendrites. These changes are age dependent and expressed only in cells >18 d in vitro (DIV). Activation of both NMDARs and AMPARs as well as a sustained rise of internal calcium levels are necessary for induction of this plasticity. On the other hand, blockade of network activity or mGluRs does not abolish the observed morphological plasticity. Electrophysiologically, a brief exposure to glutamate induces an increase in the magnitude of EPSCs evoked between pairs of neurons, as well as in mEPSC frequency and amplitude, in mature but not young cultures. These results demonstrate an age-dependent, rapid and robust morphological and functional change in cultured central neurons that may contribute to their ability to express long term synaptic plasticity.