Biblioteca Digital

The prefrontal cortex is continuously required for working memory processing during wakefulness, but is particularly hypoactivated during sleep and in psychiatric disorders such as schizophrenia. Ammon`s horn CA1 hippocampus subfield (CA1) afferents provide a functional modulatory path that is subjected to synaptic plasticity and a prominent monoaminergic influence. However, little is known about the muscarinic cholinergic effects on prefrontal synapses. Here, we investigated the effects of the muscarinic agonist, pilocarpine (PILO), on the induction and maintenance of CA1-medial prefrontal cortex (mPFC) long-term potentiation (LTP) as well as on brain monoamine levels. Field evoked responses were recorded in urethane-anesthetized rats during baseline (50 min) and after LTP (130 min), and compared with controls. LTP was induced 20 min after PILO administration (15 mg/kg, i.p.) or vehicle (NaCl 0.15 M, i.p.). In a separate group of animals, the hippocampus and mPFC were microdissected 20 min after PILO injection and used to quantify monoamine levels. Our results show that PILO potentiates the late-phase of mPFC UP without affecting either post-tetanic potentiation or early LTP (20 min). This effect was correlated with a significant decrease in relative delta (1-4 Hz) power and an increase in sigma (10-15 Hz) and gamma (2540 Hz) powers in CA1. Monoamine levels were specifically altered in the mPFC. We observed a decrease in dopamine...

O núcleo talâmico mediodorsal (Tmd) e o córtex pré-frontal (CPF) comunicam-se mutuamente, formando um circuito envolvido em funções executivas e transtornos psiquiátricos. As funções executivas estão sujeitas aos níveis de alerta gerados pela atividade oscilatória talamocortical, que por sua vez é controlada pela transmissão colinérgica. Possivelmente, a plasticidade sináptica do circuito Tmd-CPF é sensível tanto aos padrões oscilatórios do próprio circuito quanto à modulação colinérgica. Porém, esta possibilidade ainda não foi testada, muito menos dissociando-se a participação dos receptores muscarínicos e nicotínicos. Assim, nosso objetivo foi examinar como a plasticidade Tmd-CPF é modulada sob estados oscilatórios globais mediados pelo sistema colinérgico, e se esta modulação varia com os tipos de receptores recrutados. Anestesiamos ratos com uretana e implantamos um eletrodo de estimulação no Tmd, um eletrodo de registro no CPF e uma cânula de microinjeção acima do ventrículo. Emitimos 90 pulsos elétricos no Tmd (0,05 Hz) para evocação de potenciais pós-sinápticos de campo (PPSCs) basais no CPF por 30 min. Em seguida, aplicamos injeção intraventricular do agonista muscarínico pilocarpina (PILO)...

Long-term synaptic plasticity leading to enhancement in synaptic efficacy (long-term potentiation, LTP) or decrease in synaptic efficacy (long-term depression, LTD) is widely regarded as underlying learning and memory in nervous systems. LTP and LTD at excitatory neuronal synapses are observed to be induced by precise timing of pre- and postsynaptic events. Modification of synaptic transmission in long-term plasticity is a complex process involving many pathways; for example, it is also known that both forms of synaptic plasticity can be induced by various time courses of Ca2+ introduction into the postsynaptic cell. We present a phenomenological description of a two-component process for synaptic plasticity. Our dynamical model reproduces the spike time-dependent plasticity of excitatory synapses as a function of relative timing between pre- and postsynaptic events, as observed in recent experiments. The model accounts for LTP and LTD when the postsynaptic cell is voltage clamped and depolarized (LTP) or hyperpolarized (LTD) and no postsynaptic action potentials are evoked. We are also able to connect our model with the Bienenstock, Cooper, and Munro rule. We give model predictions for changes in synaptic strength when periodic spike trains of varying frequency and Poisson distributed spike trains with varying average frequency are presented pre- and postsynaptically. When the frequency of spike presentation exceeds ≈30–40 Hz...

Exposure to an enriched environment (EE) has been shown to induce cortical plasticity. Considerable amount of research is focused on the effects of EE in the hippocampus; however, effects of EE on other brain regions and the mechanisms involved are not well known. To investigate this, we induced cortical plasticity by placing mice in an EE for one month and measured the effects of EE in the anterior cingulate cortex (ACC). Here, we show that EE enhanced the expression of the plasticity gene, egr-1, in the ACC of EE animals accompanied by enhanced cingulate long-term potentiation (LTP) and decreased cingulate long-term depression (LTD). The increased NMDA receptor NR2B/NR2A subunits current ratio is associated with the plasticity seen in the ACC while total protein levels remain unchanged. Furthermore, behavioral experiments show that these mice exposed to EE demonstrate enhanced responses to acute and long-term inflammation. Our findings suggest that exposure to EE alters physiological properties within the ACC which results in enhanced responses to inflammation.

Acetylcholine is an important modulator of synaptic efficacy and is required for learning and memory tasks involving the visual cortex. In rodent visual cortex, activation of muscarinic acetylcholine receptors (mAChRs) induces a persistent long-term depression (LTD) of transmission at synapses recorded in layer 2/3 of acute slices. Although the rodent studies expand our knowledge of how the cholinergic system modulates synaptic function underlying learning and memory, they are not easily extrapolated to more complex visual systems. Here we used tree shrews for their similarities to primates, including a visual cortex with separate, defined regions of monocular and binocular innervation, to determine whether mAChR activation induces long-term plasticity. We find that the cholinergic agonist carbachol (CCh) not only induces long-term plasticity, but the direction of the plasticity depends on the subregion. In the monocular region, CCh application induces LTD of the postsynaptic potential recorded in layer 2/3 that requires activation of m3 mAChRs and a signaling cascade that includes activation of extracellular signal-regulated kinase (ERK) 1/2. In contrast, layer 2/3 postsynaptic potentials recorded in the binocular region express long-term potentiation (LTP) following CCh application that requires activation of m1 mAChRs and phospholipase C. Our results show that activation of mAChRs induces long-term plasticity at excitatory synapses in tree shrew visual cortex. However...

Activation of presynaptic cAMP-dependent protein kinase A (PKA) triggers presynaptic long-term plasticity in synapses such as cerebellar parallel fiber and hippocampal mossy fiber synapses. RIM1α, a large multidomain protein that forms a scaffold at the presynaptic active zone, is essential for presynaptic long-term plasticity in these synapses and is phosphorylated by PKA at serine-413. Previous studies suggested that phosphorylation of RIM1α at serine-413 is required for presynaptic long-term potentiation in parallel fiber synapses formed in vitro by cultured cerebellar neurons and that this type of presynaptic long-term potentiation is mediated by binding of 14-3-3 proteins to phosphorylated serine-413. To test the role of serine-413 phosphorylation in vivo, we have now produced knockin mice in which serine-413 is mutated to alanine. Surprisingly, we find that in these mutant mice, three different forms of presynaptic PKA-dependent long-term plasticity are normal. Furthermore, we observed that in contrast to RIM1α KO mice, RIM1 knockin mice containing the serine-413 substitution exhibit normal learning capabilities. The lack of an effect of the serine-413 mutation of RIM1α is not due to compensation by RIM2α because mice carrying both the serine-413 substitution and a RIM2α deletion still exhibited normal long-term presynaptic plasticity. Thus...

Different GABAergic interneuron types have specific roles in hippocampal function, and anatomical as well as physiological features vary greatly between interneuron classes. Long-term plasticity of interneurons has mostly been studied in unidentified GABAergic cells and is known to be very heterogeneous. Here we tested whether cell type-specific plasticity properties in distinct GABAergic interneuron types might underlie this heterogeneity. We show that long-term potentiation (LTP) and –depression (LTD), two common forms of synaptic plasticity, are expressed in a highly cell type-specific manner at glutamatergic synapses onto hippocampal GABAergic neurons. Both LTP and LTD are generated in interneurons expressing parvalbumin (PV+), whereas interneurons with similar axon distributions but expressing cannabinoid receptor-1 (CB1R+) show no lasting plasticity in response to the same protocol. In addition, LTP or LTD occurs in PV+ interneurons with different efferent target domains. Perisomatic-targeting PV+ basket and axo-axonic interneurons express LTP, whereas glutamatergic synapses onto PV+ bistratified cells display LTD. Both LTP and LTD are pathway-specific, independent of NMDARs and occur at synapses with calcium-permeable AMPA receptors. Plasticity in interneurons with CP-AMPARs strongly modulates disynaptic GABAergic transmission onto CA1 pyramidal cells. We propose that long-term plasticity adjusts the synaptic strength between pyramidal cells and interneurons in a cell type-specific manner and in the defined CA1 interneurons shifts the spatial pattern of inhibitory weight from pyramidal cell dendrites to the perisomatic region.

It is well established that short-term synaptic plasticity (STP) of neocortical synapses is itself plastic – e.g., the induction of LTP and LTD tend to shift STP towards short-term depression and facilitation, respectively. What has not been addressed theoretically or experimentally is whether STP is “learned”; that is, is STP regulated by specific learning rules that are in place to optimize the computations performed at synapses, or, are changes in STP essentially an epiphenomenon of long-term plasticity? Here we propose that STP is governed by specific learning rules that operate independently and in parallel of the associative learning rules governing baseline synaptic strength. We describe a learning rule for STP and, using simulations, demonstrate that it significantly enhances the discrimination of spatiotemporal stimuli. Additionally we generate a set of experimental predictions aimed at testing our hypothesis.

Neuronal development involves several discrete morphological steps requiring migration of newborn neurons to characteristic locations, extension of axons and dendrites into proper target regions, and formation of synapses with appropriate partners. Small GTPases such as Rac1, are believed to be critical regulators of these processes. We have previously reported that Rac1 is highly expressed in mouse hippocampus, where NMDA receptor activation causes Rac1 to translocate to the membrane in a manner similar to that observed in other non-neuronal cells. Additionally Rac1 has been seen to play a role in activation of signal transduction pathways associated with hippocampal learning and memory. Because of the established role of LTP and LTD in learning and memory processes, in this study we investigate whether Rac1 plays also an active and critical role in these types of long-term synaptic plasticity. We found that activation of Rac1 is associated with long-term plasticity, both LTP and LTD. Rac1 appears to have a transient role during the induction of NMDA receptor-dependent LTP, but does not have an effect on LTP maintenance and expression. Similar results were found for NMDA receptor-dependent induction of LTD, while mGluR-dependent LTD was shown to be significantly altered but not abolished. The results of these experiments provide essential knowledge regarding the signaling mechanisms that underlie synaptic plasticity...

Converging lines of evidence suggest that synaptic plasticity at auditory inputs to the lateral amygdala (LA) is critical for the formation and storage of auditory fear memories. Auditory information reaches the LA from both thalamic and cortical areas, raising the question whether they make distinct contributions to fear memory storage. Here we address this by comparing the induction of long-term potentation (LTP) at the two inputs in vivo in anesthetized rats. We first show, using field potential measurements, that different patterns and frequencies of high-frequency stimulation (HFS) consistently elicit stronger LTP at cortical inputs compared to thalamic inputs. Field potential responses elicited during HFS of thalamic inputs were also smaller compared to responses during HFS of cortical inputs, suggesting less effective postsynaptic depolarization. Pronounced differences in the short-term plasticity profiles of the two inputs were also observed: whereas cortical inputs displayed paired-pulse facilitation, thalamic inputs displayed paired-pulse depression. These differences in short-term and long-term plasticity were not due to stronger inhibition at thalamic inputs: although removal of inhibition enhanced responses to HFS, it did not enhance thalamic LTP and left paired-pulse depression unaffected. These results highlight the divergent nature of short-term and long-term plasticity at thalamic and cortical sensory inputs to the LA...

Long-term synaptic plasticity is a major cellular substrate for learning, memory, and behavioral adaptation. Although early examples of long-term synaptic plasticity described a mechanism by which postsynaptic signal transduction was potentiated, it is now apparent that there is a vast array of mechanisms for long-term synaptic plasticity that involve modifications to either or both the presynaptic terminal and postsynaptic site. In this article, we discuss current and evolving approaches to identify presynaptic mechanisms as well as discuss their limitations. We next provide examples of the diverse circuits in which presynaptic forms of long-term synaptic plasticity have been described and discuss the potential contribution this form of plasticity might add to circuit function. Finally, we examine the present evidence for the molecular pathways and cellular events underlying presynaptic long-term synaptic plasticity.

Synchrony in a presynaptic population leads to correlations in vesicle occupancy at the active sites for neurotransmitter release. The number of independent release sites per presynaptic neuron, a synaptic parameter recently shown to be modified during long-term plasticity, will modulate these correlations and therefore have a significant effect on the firing rate of the postsynaptic neuron. To understand how correlations from synaptic dynamics and from presynaptic synchrony shape the postsynaptic response, we study a model of multiple release site short-term plasticity and derive exact results for the crosscorrelation function of vesicle occupancy and neurotransmitter release, as well as the postsynaptic voltage variance. Using approximate forms for the postsynaptic firing rate in the limits of low and high correlations, we demonstrate that short-term depression leads to a maximum response for an intermediate number of presynaptic release sites, and that this leads to a tuning-curve response peaked at an optimal presynaptic synchrony set by the number of neurotransmitter release sites per presynaptic neuron. These effects arise because, above a certain level of correlation, activity in the presynaptic population is overly strong resulting in wastage of the pool of releasable neurotransmitter. As the nervous system operates under constraints of efficient metabolism it is likely that this phenomenon provides an activity-dependent constraint on network architecture.

Dopamine (DA) plays an essential role in the enablement of cognition. It adds color to experience-dependent information storage, conferring salience to the memories that result. At the synaptic level, experience-dependent information storage is enabled by synaptic plasticity, and given its importance for memory formation, it is not surprising that DA comprises a key neuromodulator in the enablement of synaptic plasticity, and particularly of plasticity that persists for longer periods of time: Analogous to long-term memory. The hippocampus, that is a critical structure for the synaptic processing of semantic, episodic, spatial, and declarative memories, is specifically affected by DA, with the D1/D5 receptor proving crucial for hippocampus-dependent memory. Furthermore, D1/D5 receptors are pivotal in conferring the properties of novelty and reward to information being processed by the hippocampus. They also facilitate the expression of persistent forms of synaptic plasticity, and given reports that both long-term potentiation and long-term depression encode different aspects of spatial representations, this suggests that D1/D5 receptors can drive the nature and qualitative content of stored information in the hippocampus. In light of these observations...

Various hippocampal and neocortical synapses of mammalian brain show both short-term plasticity and long-term plasticity, which are considered to underlie learning and memory by the brain. According to Hebb’s postulate, synaptic plasticity encodes memory traces of past experiences into cell assemblies in cortical circuits. However, it remains unclear how the various forms of long-term and short-term synaptic plasticity cooperatively create and reorganize such cell assemblies. Here, we investigate the mechanism in which the three forms of synaptic plasticity known in cortical circuits, i.e., spike-timing-dependent plasticity (STDP), short-term depression (STD) and homeostatic plasticity, cooperatively generate, retain and reorganize cell assemblies in a recurrent neuronal network model. We show that multiple cell assemblies generated by external stimuli can survive noisy spontaneous network activity for an adequate range of the strength of STD. Furthermore, our model predicts that a symmetric temporal window of STDP, such as observed in dopaminergic modulations on hippocampal neurons, is crucial for the retention and integration of multiple cell assemblies. These results may have implications for the understanding of cortical memory processes.

The subiculum (SUB) serves as the major output structure of the hippocampus; therefore, exploring synaptic plasticity within this region is of great importance for understanding the dynamics of hippocampal circuitry and hippocampal–cortical interactions. Previous research has shown exposure to acute stress dramatically alters synaptic plasticity within the hippocampus proper. Using in vivo electrophysiological recordings in urethane-anesthetized adult male Sprague–Dawley rats, we tested the effects of either acute restraint stress (30 min) or corticosterone (CORT) injections (3 mg/kg; s.c.) on short- and long-term forms of synaptic plasticity in the Cornu Ammonis 1–SUB pathway. Paired-pulse facilitation and two forms of long-term plasticity (long-term potentiation and late-developing potentiation) were significantly reduced after exposure to acute stress but not CORT treatment. Measurements of plasma CORT confirmed similar levels of circulating hormone in animals exposed to either acute stress or CORT treatment. The disruptive effects of acute stress on both short- and long-term forms of synaptic plasticity are mediated by glucocorticoid receptor (GR) activation as these disruptions were blocked by pre-treatment with the selective GR antagonist RU38486 (10 mg/kg; s.c.). The present results highlight the susceptibility of subicular plasticity to acute stress and provide evidence that GR activation is necessary but not sufficient for mediating these alterations.

Dopamine (DA) modulates glutamatergic synaptic transmission and its plasticity in the striatum; however it is not well known how DA modulates long-term plasticity of striatal GABAergic inhibitory synapses. This work focused on the analysis of both dopaminergic modulation of inhibitory synapses and the synaptic plasticity established between GABAergic afferents to medium spiny neurons (MSNs). Our results showed that low and high DA concentrations mainly reduced the amplitude of inhibitory synaptic response; however detailed analysis of the D1 and D2 participation in this modulation displayed a wide variability in synaptic response. Analyzing DA participation in striatal GABAergic plasticity we observed that high frequency stimulation (HFS) of GABAergic interneurons in the presence of DA at a low concentration (200 nM) favored the expression of inhibitory striatal LTD, whereas higher concentration of DA (20 μM) primarily induced LTP. Interestingly, the plasticity induced in an animal model of striatal degeneration mimicked that induced in the presence of DA at a high concentration, which was not abolished with D2 antagonist but was prevented by PKA blocker.

La mémoire et l’apprentissage sont des phénomènes complexes dont on ne comprend pas encore bien l’origine au niveau cellulaire et moléculaire. Cependant, il est largement admis que des changements plus simples au niveau synaptique, tels que la potentialisation à long-terme (long-term potentiation ou LTP) pourraient constituer la base cellulaire de la formation des nouveaux souvenirs. Ces mécanismes sont couramment étudiés au niveau de l’hippocampe, une région du lobe temporal reconnue comme étant nécessaire à la formation de la mémoire explicite chez les mammifères. La LTP est classiquement définie comme un renforcement durable de l’efficacité de connexions synaptiques ayant été stimulées de façon répétée et soutenue. De plus, on peut distinguer deux formes de LTP: une LTP précoce, qui repose sur la modification de protéines déjà formées, et une LTP tardive, qui requiert, elle, la synthèse de nouvelles protéines. Cependant, bien que de nombreuses études se soient intéressées au rôle de la traduction pour la maintenance de la LTP, les mécanismes couplant l’activité synaptique à la machinerie de synthèse protéique, de même que l’identité des protéines requises sont encore peu connus. Dans cette optique...

Plasticity of synapses is not static across the lifespan. As the brain matures and ages, the ability of neurons to undergo structural and functional change becomes more limited. Further, there are a number of modulatory factors that influence the expression of synaptic plasticity. Here, three approaches were taken to examine and manipulate plasticity in the auditory thalamocortical system of rats. Using an in vivo preparation, long-term potentiation (LTP) and paired pulse (PP) responses were used as measures of long- and short-term plasticity, respectively. First, the effect of intracortical zinc application in the primary auditory cortex (A1) on LTP was examined. Following theta burst stimulation (TBS) of the medial geniculate nucleus (MGN), juvenile and middle-age rats, but not young adults, showed greater levels of LTP with zinc application relative to age-matched control animals. Next, PP responses were examined between rats reared in unaltered acoustic conditions and those reared in continuous white noise (WN) from postnatal day (PD) 5 to PD 50-60 (i.e., subjected to patterned sound deprivation). Rats reared in WN demonstrated less PP depression relative to controls, indicating that WN rearing alters short-term thalamocortical synaptic responses. Furthermore...

Far from being static transmission units, synapses are highly dynamical elements that change over multiple time scales depending on the history of the neural activity of both the pre- and postsynaptic neuron. Moreover, synaptic changes on different time scales interact: long-term plasticity (LTP) can modify the properties of short-term plasticity (STP) in the same synapse. Most existing theories of synaptic plasticity focus on only one of these time scales (either STP or LTP or late-LTP) and the theoretical principles underlying their interactions are thus largely unknown. Here we develop a normative model of synaptic plasticity that combines both STP and LTP and predicts specific patterns for their interactions. Recently, it has been proposed that STP arranges for the local postsynaptic membrane potential at a synapse to behave as an optimal estimator of the presynaptic membrane potential based on the incoming spikes. Here we generalize this approach by considering an optimal estimator of a non-linear function of the membrane potential and the long-term synaptic efficacy -- which itself may be subject to change on a slower time scale. We find that an increase in the long-term synaptic efficacy necessitates changes in the dynamics of STP. More precisely...