PACAP-38 enhances excitatory synaptic transmission in the rat hippocampal CA1 region

Specific receptors for pituitary adenylate cyclase-activating polypeptide (PACAP), a novel peptide with neuroregulatory and neurotrophic functions, have been identified recently in different brain regions, including the hippocampus. In this study, we examined the effects of PACAP-38 on the excitatory postsynaptic field potentials (fEPSPs) evoked at the Schaffer collateral-CA1 synapses. Brief bath application of PACAP-38 (0.05 nM) induced a long-lasting facilitation of the basal transmission. Enhancement of this response was occluded in part by previous high-frequency-induced long-term potentiation (LTP). PACAP-38 did not significantly alter the paired-pulse facilitation (PPF). PACAP-38 has been shown to have a presynaptic effect on the septohippocampal cholinergic terminals, which results in an increase in basal acetylcholine (ACh) release. To assess whether the PACAP-38 enhancement of CA1 synapses was related to the activation of the cholinergic system we examined the effect of this peptide in the presence of atropine, a muscarinic receptor antagonist. The enhancement of the fEPSPs by PACAP-38 was blocked by bath application of atropine. These results show that PACAP-38 induces facilitation of hippocampal synaptic transmission through activation of the cholinergic system via the muscarinic receptors.     

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.     

Ontogenetic changes in the neural mechanisms of eyeblink conditioning

The rodent eyeblink conditioning paradigm is an ideal model system for examining the relationship between neural maturation and the ontogeny of associative learning. Elucidation of the neural mechanisms underlying the ontogeny of learning is tractable using eyeblink conditioning because the necessary neural circuitry (cerebellum and interconnected brainstem nuclei) underlying the acquisition and retention of the conditioned response (CR) has been identified in adult organisms. Moreover, the cerebellum exhibits substantial postnatal anatomical and physiological maturation in rats. The eyeblink CR emerges developmentally between postnatal day (PND) 17 and 24 in rats. A series of experiments found that the ontogenetic emergence of eyeblink conditioning is related to the development of associative learning and not related to changes in performance. More recent studies have examined the relationship between the development of eyeblink conditioning and the physiological maturation of the cerebellum, a brain structure that is necessary for eyeblink conditioning in adult organisms. Disrupting cerebellar development with lesions or antimitotic treatments impairs the ontogeny of eyeblink conditioning. Studies of the development of physiological processes within the cerebellum have revealed striking ontogenetic changes in stimulus-elicited and learning-related neuronal activity. Neurons in the interpositus nucleus and Purkinje cells in the cortex exhibit developmental increases in neuronal discharges following the unconditioned stimulus (US) and in neuronal discharges that model the amplitude and time-course of the eyeblink CR. The developmental changes in CR-related neuronal activity in the cerebellum suggest that the ontogeny of eyeblink conditioning depends on the development of mechanisms that estavlish cerebellar plasticity. Learning and the induction of neural plasticity depend on the magnitude of the US input to the cerebellum. The role of developmental changes in the efficacy of the US pathway has been investigated by monitoring neuronal activity in the inferior olive and with stimulation techniques. The results of these experiments indicate that the development of the conditioned eyeblink response may depend on dynamic interactions between multiple developmental processes within the eyeblink neural circuitry.     

Whereas short-term facilitation is presynaptic, intermediate-term facilitation involves both presynaptic and postsynaptic protein kinases and protein synthesis

Whereas short-term plasticity involves covalent modifications that are generally restricted to either presynaptic or postsynaptic structures, long-term plasticity involves the growth of new synapses, which by its nature involves both pre- and postsynaptic alterations. In addition, an intermediate-term stage of plasticity has been identified that might form a bridge between short- and long-term plasticity. Consistent with that idea, although short-term term behavioral sensitization in Aplysia involves presynaptic mechanisms, intermediate-term sensitization involves both pre- and postsynaptic mechanisms. However, it has not been known whether that is also true of facilitation in vitro, where a more detailed analysis of the mechanisms involved in the different stages and their interrelations is feasible. To address those questions, we have examined pre- and postsynaptic mechanisms of short- and intermediate-term facilitation at Aplysia sensory-motor neuron synapses in isolated cell culture. Whereas short-term facilitation by 1-min 5-HT involves presynaptic PKA and CamKII, intermediate-term facilitation by 10-min 5-HT involves presynaptic PKC and postsynaptic Ca(2+) and CamKII, as well as both pre- and postsynaptic protein synthesis. These results support the idea that the intermediate-term stage is the first to involve both pre- and postsynaptic molecular mechanisms, which could in turn serve as some of the initial steps in a cascade leading to synaptic growth during long-term plasticity.     

Chronic nicotine exposure induces a long-lasting and pathway-specific facilitation of LTP in the amygdala

Nicotine, in the form of tobacco, is the most commonly used drug of abuse. In addition to its rewarding properties, nicotine also affects many cognitive and emotional processes that involve several brain regions, including hippocampus and amygdala. Long-term changes in synaptic strength in these brain regions after drug exposure may be importantly correlated with behavioral changes induced by nicotine. Here, we study the effect of chronic oral administration of nicotine on the long-term synaptic potentiation in the amygdala, a key structure for emotional memory. We find that oral administration of nicotine for 7 d produces a significant enhancement of LTP in the amygdala. This facilitation is pathway specific: Nicotine selectively facilitates LTP in the cortical-lateral amygdala pathway, but not the thalamic-lateral and the lateral-basolateral synaptic pathway. The synaptic facilitation induced by a 7-d exposure to nicotine is long-lasting, it persists for 72 h after cessation of nicotine but decays 8 d after its cessation. In contrast, a shorter exposure of nicotine (24 h) induces only a short-lasting facilitation of synaptic plasticity that dissipates 24 and 72 h after cessation of nicotine. The facilitation of LTP in the amygdala after exposure to nicotine is mediated by removal of GABAergic inhibition, is dependent on the activation NMDA receptors, and can be prevented by blocking either α7 or β2 nACh receptors. Our results indicate that chronic exposure to nicotine can promote the induction of long-lasting modifications of synapses in a specific pathway in the amygdala.These changes in synaptic plasticity may contribute to the complex neural adaptations and behaviors caused by nicotine.     

Ontogenetic Changes in the Neural Mechanisms of Eyeblink Conditioning

The rodent eyeblink conditioning paradigm is an ideal model system for examining the relationship between neural maturation and the ontogeny of associative learning. Elucidation of the neural mechanisms underlying the ontogeny of learning is tractable using eyeblink conditioning because the necessary neural circuitry (cerebellum and interconnected brainstem nuclei) underlying the acquisition and retention of the conditioned response (CR) has been identified in adult organisms. Moreover, the cerebellum exhibits substantial postnatal anatomical and physiological maturation in rats. The eyeblink CR emerges developmentally between postnatal day (PND) 17 and 24 in rats. A series of experiments found that the ontogenetic emergence of eyeblink conditioning is related to the development of associative learning and not related to changes in performance. More recent studies have examined the relationship between the development of eyeblink conditioning and the physiological maturation of the cerebellum, a brain structure that is necessary for eyeblink conditioning in adult organisms. Disrupting cerebellar development with lesions or antimitotic treatments impairs the ontogeny of eyeblink conditioning. Studies of the development of physiological processes within the cerebellum have revealed striking ontogenetic changes in stimulus-elicited and learning-related neuronal activity. Neurons in the interpositus nucleus and Purkinje cells in the cortex exhibit developmental increases in neuronal discharges following the unconditioned stimulus (US) and in neuronal discharges that model the amplitude and time-course of the eyeblink CR. The developmental changes in CR-related neuronal activity in the cerebellum suggest that the ontogeny of eyeblink conditioning depends on the development of mechanisms that establish cerebellar plasticity. Learning and the induction of neural plasticity depend on the magnitude of the US input to the cerebellum. The role of developmental changes in the efficacy of the US pathway has been investigated by monitoring neuronal activity in the inferior olive and with stimulation techniques. The results of these experiments indicate that the development of the conditioned eyeblink response may depend on dynamic interactions between multiple developmental processes within the eyeblink neural circuitry.     

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.     

Calcium signaling in mitral cell dendrites of olfactory bulbs of neonatal rats and mice during olfactory nerve Stimulation and beta-adrenoceptor activation

Synapses formed by the olfactory nerve (ON) provide the source of excitatory synaptic input onto mitral cells (MC) in the olfactory bulb. These synapses, which relay odor-specific inputs, are confined to the distally tufted single primary dendrites of MCs, the first stage of central olfactory processing. beta-adrenergic modulation of electrical and chemical signaling at these synapses may be involved in early odor preference learning. To investigate this possibility, we combined electrophysiological recordings with calcium imaging in olfactory bulb slices prepared from neonatal rats and mice. Activation of ON-MC synapses induced postsynaptic potentials, which were associated with large postsynaptic calcium transients. Neither electrical nor calcium responses were affected by beta-adrenergic agonists or antagonist. Immunocytochemical analysis of MCs and their tufted dendrites revealed clear immunoreactivity with antibodies against alpha1A (Cav2.1, P/Q-type) and alpha1B (Cav2.2, N-type), but not against alpha1C (Cav1.2, L-type) or alpha1D (Cav1.3, L-type) calcium channel subunits. Moreover, nimodipine, a blocker of L-type calcium channels, had no effect on either electrical or calcium signaling at ON-MC synapses. In contrast to previous evidence, we concluded that in neonatal rats and mice (P5-P8), mitral cells do not express significant amounts of L-type calcium channels, the calcium channel type that is often targeted by beta-adrenergic modulation. The absence of beta-adrenergic modulation on either electrical or calcium signaling at ON-MC synapses of neonatal rats and mice excludes the involvement of this mechanism in early odor preference learning.     

Enhancement of glutamate release by L-fucose changes effects of glutamate receptor antagonists on long-term potentiation in the rat hippocampus

In previous studies L-fucose has been shown to facilitate long-term memory formation and to enhance and prolong long-term potentiation (LTP). To search for possible presynaptic or postsynaptic mechanisms that are affected by L-fucose, we examined the effect of L-fucose on (1) inhibition of LTP induction via glutamate receptors by antagonists, (2) paired-pulse facilitation, and (3) presynaptic transmitter release. Coapplication of 0.2 mM L-fucose with the competitive N-methyl-D-aspartate (NMDA) receptor antagonist, D-2-amino-5-phosphonovalerate (AP5), or coapplication of 0.2 mM L-fucose in the presence of an inhibitor for class I/II metabotropic glutamate receptors, (S)-alpha-methyl-4-carboxyphenylglycine (MCPG), reversed LTP blockade in the CA1-region of hippocampal slices. In contrast, L-fucose had no effect on the LTP blockade by the noncompetitive NMDA ion-channel blocker (5R,10S)-(+)-5-Methyl-10, 11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine hydrogen maleate (MK-801). Paired-pulse facilitation, which is a primarily presynaptic phenomenon of short-term plasticity, was decreased in the presence of 0.2 mM L-fucose. Furthermore, L-fucose enhanced the K(+)-stimulated release of [(3)H]-D-aspartate from preloaded hippocampal slices in a concentration-dependent manner. These observations demonstrate an influence of L-fucose on transmitter release that in turn can increase transmitter availability at postsynaptic glutamate receptors. This effect of L-fucose may contribute to the LTP facilitation seen in vitro and in vivo as well as to improvement in memory formation.     

儿童青少年认知能力发展与脑发育

自发展认知神经科学兴起以来, 研究者就开始借助MRI等脑成像技术探讨儿童青少年认知能力发展与大脑结构发育和功能特点等之间的关系, 这为揭示行为发展与生理成熟之间的关系、儿童认知发展的神经活动规律、正常和障碍群体的独特大脑神经结构及活动特点等提供了重要启示。通过对有关儿童青少年智力、工作记忆、反应抑制等认知能力发展与大脑结构发育、大脑功能发育之间关系, 以及认知能力训练与大脑可塑性等研究的介绍, 指出发展认知神经科学的未来研究应重视采用纵向设计, 关注自然成熟和经验对正常或障碍儿童青少年认知发展与脑发育关系的交互影响, 同时从练习和训练的角度对大脑可塑性的特点进行探讨。     

Synaptogenesis and heritable aspects of executive attention

In humans, changes in brain structure and function can be measured non-invasively during postnatal development. In animals, advanced optical imaging measures can track the formation of synapses during learning and behavior. With the recent progress in these technologies, it is appropriate to begin to assess how the physiological processes of synapse, circuit, and neural network formation relate to the process of cognitive development. Of particular interest is the development of executive function, which develops more gradually in humans. One approach that has shown promise is molecular genetics. The completion of the human genome project and the human genome diversity project make it straightforward to ask whether variation in a particular gene correlates with variation in behavior, brain structure, brain activity, or all of the above. Strategies that unify the wealth of biochemical knowledge pertaining to synapse formation with the functional measures of brain structure and activity may lead to new insights in developmental cognitive psychology.     

Coincident induction of long-term facilitation at sensory-motor synapses in Aplysia: presynaptic and postsynaptic factors

Induction of long-term synaptic changes at one synapse can facilitate the induction of long-term plasticity at another synapse. Here we show that if Aplysia sensory neuron (SN) somata and their remote motor neuron (MN) synapses are simultaneously exposed to serotonin (5HT) pulses, which at either site alone are insufficient to induce long-term facilitation (LTF), processes activated at these sites interact to induce LTF. Coincident induction of LTF requires: (1) that the synaptic pulse occurs within a brief temporal window of the somatic pulse and (2) that local protein synthesis occurs immediately at the synapse, followed by delayed protein synthesis at the soma. LTF at the SN-MN synapses can also be induced with cell-wide application of repeated pulses of 5HT. However, these two forms of LTF differ mechanistically: (1) coincident LTF requires protein synthesis in the postsynaptic motor neuron, whereas repeated 5HT LTF does not, and (2) repeated 5HT LTF is accompanied by intermediate-term (3 h) facilitation, whereas coincident LTF is not. Thus LTF expressed in the same temporal domain can result from different underlying mechanisms.     

Interactions between Depression and Facilitation within Neural Networks: Updating the Dual-Process Theory of Plasticity

Repetitive stimulation often results in habituation of the elicited response. However, if the stimulus is sufficiently strong, habituation may be preceded by transient sensitization or even replaced by enduring sensitization. In 1970, Groves and Thompson formulated the dual-process theory of plasticity to explain these characteristic behavioral changes on the basis of competition between decremental plasticity (depression) and incremental plasticity (facilitation) occurring within the neural network. Data from both vertebrate and invertebrate systems are reviewed and indicate that the effects of depression and facilitation are not exclusively additive but, rather, that those processes interact in a complex manner. Serial ordering of induction of learning, in which a depressing locus precedes the modulatory system responsible for inducing facilitation, causes the facilitation to wane. The parallel and/or serial expression of depression and waning facilitation within the stimulus–response pathway culminates in the behavioral changes that characterize dual-process learning. A mathematical model is presented to formally express and extend understanding of the interactions between depression and facilitation.     

Neonatal auditory evoked responses are related to perinatal maternal anxiety

Maternal stress and anxiety during pregnancy are related to negative developmental outcomes for offspring, both physiological and psychological, from the fetal period through early adolescence. This robust relationship is likely to be partly explained by alterations in fetal neurodevelopmental programming, calling for further examination of neurophysiologically-based cognitive markers that may be related to the altered structure–function relationships that contribute to these negative developmental outcomes. The current investigation examined the relationship between perinatal maternal anxiety and neonatal auditory evoked responses (AERs) to mother and stranger voices. Results indicated that neonates of low-anxiety mothers displayed more negative frontal slow wave amplitudes in response to their mother’s voice compared to a female stranger’s voice, while neonates of high-anxiety mothers showed the opposite pattern. These findings suggest that neonates of perinatally anxious mothers may demonstrate neurophysiologically-based differences in attentional allocation. This could represent one pathway to the negative psychological outcomes seen throughout development in offspring of anxious mothers.     

Neonatal auditory evoked responses are related to perinatal maternal anxiety

Maternal stress and anxiety during pregnancy are related to negative developmental outcomes for offspring, both physiological and psychological, from the fetal period through early adolescence. This robust relationship is likely to be partly explained by alterations in fetal neurodevelopmental programming, calling for further examination of neurophysiologically-based cognitive markers that may be related to the altered structure–function relationships that contribute to these negative developmental outcomes. The current investigation examined the relationship between perinatal maternal anxiety and neonatal auditory evoked responses (AERs) to mother and stranger voices. Results indicated that neonates of low-anxiety mothers displayed more negative frontal slow wave amplitudes in response to their mother’s voice compared to a female stranger’s voice, while neonates of high-anxiety mothers showed the opposite pattern. These findings suggest that neonates of perinatally anxious mothers may demonstrate neurophysiologically-based differences in attentional allocation. This could represent one pathway to the negative psychological outcomes seen throughout development in offspring of anxious mothers.     

Type-based associations in grapheme-color synaesthesia revealed by response time distribution analyses

Determining the nature of binding in grapheme-color synaesthesia has consequences for understanding the neural basis of synaesthesia and visual awareness in general. We evaluated type- and token-based letter-color binding using a synaesthetic version of the object-reviewing paradigm. Although mean response times failed to reveal any significant differences between synaesthetes and control participants, RT analyses with ex-Gaussian distributions revealed that the response facilitation in the synaesthesia group reflected type representations exclusively, while response facilitation in the control group, who learned letter-color associations, was dominated by token representations. Thus, letter-color associations in associator synaesthetes are type-based, and do not involve binding to object tokens, consistent with their subjective reports. Contrary to recent studies that failed to find differences between synaesthetes and non-synaesthetes with behavioral measures, response time distribution analyses indicate that color sensations in synaesthetes are not simply the extreme form of normal letter-color associations, and cannot be attributed to demand characteristics.     

The acquisition of an appetite

Unlike older animals, weanling-age rats do not seek water to drink when they are dehydrated, despite the fact that a physiological sensitivity to dehydration is present very soon after birth. We demonstrate here that the appetitive behaviors needed to approach and obtain water become linked to dehydration only as a result of specific postnatal learning experience. Preventing early experience with dehydration retards the developmental emergence of dehydration-induced, water-oriented behavior in young rats. But a single pairing of water with dehydration can establish an appetitive response. These findings reveal a critical role of early learning in the development of goal-oriented behavior. Such a learning process is potentially characteristic of other behavioral systems, from the most basic appetites to complex motives.     

Galpha(i2) inhibition of adenylate cyclase regulates presynaptic activity and unmasks cGMP-dependent long-term depression at Schaffer collateral-CA1 hippocampal synapses

Cyclic AMP signaling plays a central role in regulating activity at a number of synapses in the brain. We showed previously that pairing activation of receptors that inhibit adenylate cyclase (AC) and reduce the concentration of cyclic AMP, with elevation of the concentration of cyclic GMP is sufficient to elicit a presynaptically expressed form of LTD at Schaffer collateral-CA1 synapses in the hippocampus. To directly test the role of AC inhibition and G-protein signaling in LTD at these synapses, we utilized transgenic mice that express a mutant, constitutively active inhibitory G protein, Galpha(i2), in principal neurons of the forebrain. Transgene expression of Galpha(i2) markedly enhanced LTD and impaired late-phase LTP at Schaffer collateral synapses, with no associated differences in input/output relations, paired-pulse facilitation, or NMDA receptor-gated conductances. When paired with application of a type V phosphodiesterase inhibitor to elevate the concentration of intracellular cyclic GMP, constitutively active Galpha(i2) expression converted the transient depression normally caused by this treatment to an LTD that persisted after the drug was washed out. Moreover, this effect could be mimicked in control slices by pairing type V phosphodiesterase inhibitor application with application of a PKA inhibitor. Electrophysiological recordings of spontaneous excitatory postsynaptic currents and two-photon visualization of vesicular release using FM1-43 revealed that constitutively active Galpha(i2) tonically reduced basal release probability from the rapidly recycling vesicle pool of Schaffer collateral terminals. Our findings support the hypothesis that inhibitory G-protein signaling acts presynaptically to regulate release, and, when paired with elevations in the concentration of cyclic GMP, converts a transient cyclic GMP-induced depression into a long-lasting decrease in release.     

Adolescents' Reward‐related Neural Activation: Links to Thoughts of Nonsuicidal Self‐Injury

Adolescence is a critical developmental period marked by an increase in risk behaviors, including nonsuicidal self‐injury (NSSI). Heightened reward‐related brain activation and relatively limited recruitment of prefrontal regions contribute to the initiation of risky behaviors in adolescence. However, neural reward processing has not been examined among adolescents who are at risk for future engagement for NSSI specifically, but who have yet to actually engage in this behavior. In the current fMRI study (N = 71), we hypothesized that altered reward processing would be associated with adolescents' thoughts of NSSI. Results showed that NSSI youth exhibited heightened activation in the bilateral putamen in response to a monetary reward. This pattern of findings suggests that heightened neural sensitivity to reward is associated with thoughts of NSSI in early adolescence. Implications for prevention are discussed.     

Can mismatch negativity be linked to synaptic processes? A glutamatergic approach to deviance detection

This article aims to provide a theoretical framework to elucidate the neurophysiological underpinnings of deviance detection as reflected by mismatch negativity. A six-step model of the information processing necessary for deviance detection is proposed. In this model, predictive coding of learned regularities is realized by means of long-term potentiation with a crucial role for NMDA receptors. Mismatch negativity occurs at the last stage of the model, reflecting the increase in free energy associated with the switching on of silent synapses and the formation of new neural circuits required for adaptation to the environmental deviance. The model is discussed with regard to the pathological states most studied in relation to mismatch negativity: alcohol intoxication, alcohol withdrawal, and schizophrenia.