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J Neurosci [journal]
- eIF2α Dephosphorylation in Basolateral Amygdala Mediates Reconsolidation of Drug Memory. [Journal Article]
- J Neurosci 2014 Jul 23; 34(30):10010-21.
Maladaptive memories elicited by exposure to environmental stimuli associated with drugs of abuse are often responsible for relapse among addicts. Interference with the reconsolidation of drug memory can inhibit drug seeking. Previous studies have indicated that the dephosphorylation of the eukaryotic initiation factor 2 α-subunit (eIF2α) plays an important role in synaptic plasticity and long-term memory consolidation, but its role in the reconsolidation of drug memory remains unknown. The amygdala is required for the reconsolidation of a destabilized drug memory after retrieval of drug-paired stimuli. Here, we used conditioned place preference (CPP) and self-administration procedures to determine whether amygdala eIF2α dephosphorylation is required for the reconsolidation of morphine and cocaine memories in rats. We found that the levels of eIF2α phosphorylation (Ser51) and activating transcription factor 4 (ATF4) were decreased after reexposure to a previously morphine- or cocaine-paired context (i.e., a memory retrieval procedure) in the basolateral amygdala (BLA) but not in the central amygdala. Intra-BLA infusions of Sal003, a selective inhibitor of eIF2α dephosphorylation, immediately after memory retrieval disrupted the reconsolidation of morphine- or cocaine-induced CPP, leading to a long-lasting suppression of drug-paired stimulus-induced craving. Advanced knockdown of ATF4 expression in the BLA by lentivirus-mediated short-hairpin RNA blocked the disruption of the reconsolidation of morphine-induced CPP induced by Sal003 treatment. Furthermore, inhibition of eIF2α dephosphorylation in the BLA immediately after light/tone stimulus retrieval decreased subsequent cue-induced heroin-seeking behavior in the self-administration procedure. These results demonstrate that eIF2α dephosphorylation in the BLA mediates the memory reconsolidation of drug-paired stimuli.
- Glycine transporter-1 controls nonsynaptic inhibitory actions of glycine receptors in the neonatal rat hippocampus. [Journal Article]
- J Neurosci 2014 Jul 23; 34(30):10003-9.
Although functional glycinergic synapses have not been identified in the hippocampus, neurons in this area express Cl(-) permeable extrasynaptic glycine receptors (GlyRs). In experiments on CA3 pyramidal neurons on postnatal day 0-6 rat hippocampal slices, we detected robust GlyR activity as a tonic current and as single-channel events. Glycine release was independent of neuronal activity or extracellular Ca(2+). The endogenous GlyR activity was strongly enhanced by inhibition of the glycine-transporter-1 (GlyT1). Blockade of GlyT1 also caused a profound increase in the baseline current induced by exogenous glycine. Inhibition of GlyT1 reduced the frequency of spontaneous network events known as field giant depolarizing potentials (fGDPs) and of the unit activity in the absence of synaptic transmission. This inhibitory action on fGDPs was mimicked by applying 2 μm glycine or 0.1 μm isoguvacine, a GABAA-receptor agonist. Furthermore, 2 μm glycine suppressed unit spiking in the absence of synaptic transmission. Hence, despite the well known depolarizing Cl(-) equilibrium potential of neonatal hippocampal neurons, physiologically relevant extracellular glycine concentrations can exert an inhibitory action. The present data show that, akin to GABA uptake, GlyT1 exerts a powerful modulatory action on network events in the newborn hippocampus.
- Attentional modulation of the inner ear: a combined otoacoustic emission and EEG study. [Journal Article]
- J Neurosci 2014 Jul 23; 34(30):9995-10002.
Attending to a single stimulus in a complex multisensory environment requires the ability to select relevant information while ignoring distracting input. The underlying mechanism and involved neuronal levels of this attentional gain control are still a matter of debate. Here, we investigated the influence of intermodal attention on different levels of auditory processing in humans. It is known that the activity of the cochlear amplifier can be modulated by efferent neurons of the medial olivocochlear complex. We used distortion product otoacoustic emission (DPOAE) measurements to monitor cochlear activity during an intermodal cueing paradigm. Simultaneously, central auditory processing was assessed by electroencephalography (EEG) with a steady-state paradigm targeting early cortical responses and analysis of alpha oscillations reflecting higher cognitive control of attentional modulation. We found effects of selective attention at all measured levels of the auditory processing: DPOAE levels differed significantly between periods of visual and auditory attention, showing a reduction during visual attention, but no change during auditory attention. Primary auditory cortex activity, as measured by the auditory steady-state response (ASSR), differed between conditions, with higher ASSRs during auditory than visual attention. Furthermore, the analysis of cortical oscillatory activity revealed increased alpha power over occipitoparietal and frontal regions during auditory compared with visual attention, putatively reflecting suppression of visual processing. In conclusion, this study showed both enhanced processing of attended acoustic stimuli in early sensory cortex and reduced processing of distracting input, both at higher cortical levels and at the most peripheral level of the hearing system, the cochlea.
- Developmental switch of leptin signaling in arcuate nucleus neurons. [Journal Article]
- J Neurosci 2014 Jul 23; 34(30):9982-94.
Leptin is well known for its role in the regulation of energy homeostasis in adults, a mechanism that at least partially results from the inhibition of the activity of NPY/AgRP/GABA neurons (NAG) in the arcuate nucleus of the hypothalamus (ARH). During early postnatal development in the rodent, leptin promotes axonal outgrowth from ARH neurons, and preautonomic NAG neurons are particularly responsive to leptin's trophic effects. To begin to understand how leptin could simultaneously promote axonal outgrowth from and inhibit the activity of NAG neurons, we characterized the electrochemical effects of leptin on NAG neurons in mice during early development. Here, we show that NAG neurons do indeed express a functional leptin receptor throughout the early postnatal period in the mouse; however, at postnatal days 13-15, leptin causes membrane depolarization in NAG neurons, rather than the expected hyperpolarization. Leptin action on NAG neurons transitions from stimulatory to inhibitory in the periweaning period, in parallel with the acquisition of functional ATP-sensitive potassium channels. These findings are consistent with the idea that leptin provides an orexigenic drive through the NAG system to help rapidly growing pups meet their energy requirements.
- Implicit perceptual memory modulates early visual processing of ambiguous images. [Journal Article]
- J Neurosci 2014 Jul 23; 34(30):9970-81.
The way we perceive the present visual environment is influenced by past visual experiences. Here we investigated the neural basis of such experience dependency. We repeatedly presented human observers with an ambiguous visual stimulus (structure-from-motion) that can give rise to two distinct perceptual interpretations. Past visual experience is known to influence the perception of such stimuli. We recorded fast dynamics of neural activity shortly after stimulus onset using event-related electroencephalography. The number of previous occurrences of a certain percept modulated early posterior brain activity starting as early as 50 ms after stimulus onset. This modulation developed across hundreds of percept repetitions, reflecting several minutes of accumulating perceptual experience. Importantly, there was no such modulation when the mere number of previous stimulus presentations was considered regardless of how they were perceived. This indicates that the effect depended on previous perception rather than previous visual input. The short latency and posterior scalp location of the effect suggest that perceptual history modified bottom-up stimulus processing in early visual cortex. We propose that bottom-up neural responses to a given visual presentation are shaped, in part, by feedback modulation that occurred during previous presentations, thus allowing these responses to be biased in light of previous perceptual decisions.
- Differential Neuronal Representation of Spatial Attention Dependent on Relative Target Locations during Multiple Object Tracking. [Journal Article]
- J Neurosci 2014 Jul 23; 34(30):9963-9.
Humans can simultaneously track multiple moving objects with attention. The number of objects that can be tracked is known to be larger when visual stimuli are presented bilaterally rather than presented unilaterally. To elucidate the underlying neuronal mechanism, we trained monkeys to covertly track a single or multiple object(s). We found that neurons in the lateral prefrontal cortex exhibited greater activity for the target passing through the receptive field (RF) than for distractors. During multiple-object tracking, response enhancement for one target presented in the RF was stronger when the other target was located in the opposite than the same visual hemifield. Because the neuronal modulation did not differ depending on relative target locations with respect to upper and lower visual hemifields, the distance between the targets does not explain the results. We propose that inherent, anatomical separation of visual processing for contralateral and ipsilateral visual fields might constrain cognitive capacity.
- AAVshRNA-Mediated Suppression of PTEN in Adult Rats in Combination with Salmon Fibrin Administration Enables Regenerative Growth of Corticospinal Axons and Enhances Recovery of Voluntary Motor Function after Cervical Spinal Cord Injury. [Journal Article]
- J Neurosci 2014 Jul 23; 34(30):9951-62.
Conditional genetic deletion of phosphatase and tensin homolog (PTEN) in the sensorimotor cortex of neonatal mice enables regeneration of corticospinal tract (CST) axons after spinal cord injury (SCI). The present study addresses three questions: (1) whether PTEN knockdown in adult rats by nongenetic techniques enables CST regeneration, (2) whether interventions to enable CST regeneration enhance recovery of voluntary motor function, and (3) whether delivery of salmon fibrin into the injury site further enhances CST regeneration and motor recovery. Adult rats were trained in a staircase-reaching task and then received either intracortical injections of AAVshPTEN to delete PTEN or a control vector expressing shRNA for luciferase (AAVshLuc). Rats then received cervical dorsal hemisection injuries and salmon fibrin was injected into the injury site in half the rats, yielding four groups (AAVshPTEN, AAVshLuc, AAVshPTEN + fibrin, and AAVshLuc + fibrin). Forepaw function was assessed for 10 weeks after injury and CST axons were traced by injecting biotin-conjugated dextran amine into the sensorimotor cortex. Rats that received AAVshPTEN alone did not exhibit improved motor function, whereas rats that received AAVshPTEN and salmon fibrin had significantly higher forelimb-reaching scores. Tract tracing revealed that CST axons extended farther caudally in the group that received AAVshPTEN and salmon fibrin versus other groups. There were no significant differences in lesion size between the groups. Together, these data suggest that the combination of PTEN deletion and salmon fibrin injection into the lesion can significantly improve voluntary motor function after SCI by enabling regenerative growth of CST axons.
- Cocaine Abuse in Humans Is Not Associated with Increased Microglial Activation: An 18-kDa Translocator Protein Positron Emission Tomography Imaging Study with [11C]PBR28. [Journal Article]
- J Neurosci 2014 Jul 23; 34(30):9945-50.
Basic science investigations have consistently shown that repeated exposure to psychostimulant drugs, such as cocaine, activate the immune response and lead to inflammatory changes in the brain. No previous in vivo studies have confirmed this observation in chronic cocaine-abusing humans. To test this hypothesis, we used positron emission tomography imaging to measure the binding of [(11)C]PBR28 to the 18 kDa translocator protein (TSPO), a marker for microglial activation in a group of 15 recently abstinent cocaine abusers and 17 matched healthy controls. [(11)C]PBR28 volumes of distribution expressed relative to total plasma ligand concentration (VT) were measured in subjects with kinetic analysis using the arterial input function. Subjects were also genotyped for the TSPO alanine147 threonine (Ala147Thr, rs6971) polymorphism that has been shown to influence the in vivo binding of PBR28 to TSPO. Consistent with previous reports, the TSPO Ala147Thr genotype predicted the in vivo binding of [(11)C]PBR28. No significant differences in [(11)C]PBR28 VT were observed in the cortical and subcortical regions in cocaine abusers compared with healthy controls. The results of this in vivo study do not support increased TSPO expression and, by extension, microglial activation in chronic cocaine-abusing humans. Further research with more direct markers of microglial activation is necessary to conclusively rule out neuroinflammation in cocaine dependence.
- Neuronal Ensemble Synchrony during Human Focal Seizures. [Journal Article]
- J Neurosci 2014 Jul 23; 34(30):9927-44.
Seizures are classically characterized as the expression of hypersynchronous neural activity, yet the true degree of synchrony in neuronal spiking (action potentials) during human seizures remains a fundamental question. We quantified the temporal precision of spike synchrony in ensembles of neocortical neurons during seizures in people with pharmacologically intractable epilepsy. Two seizure types were analyzed: those characterized by sustained gamma (∼40-60 Hz) local field potential (LFP) oscillations or by spike-wave complexes (SWCs; ∼3 Hz). Fine (<10 ms) temporal synchrony was rarely present during gamma-band seizures, where neuronal spiking remained highly irregular and asynchronous. In SWC seizures, phase locking of neuronal spiking to the SWC spike phase induced synchrony at a coarse 50-100 ms level. In addition, transient fine synchrony occurred primarily during the initial ∼20 ms period of the SWC spike phase and varied across subjects and seizures. Sporadic coherence events between neuronal population spike counts and LFPs were observed during SWC seizures in high (∼80 Hz) gamma-band and during high-frequency oscillations (∼130 Hz). Maximum entropy models of the joint neuronal spiking probability, constrained only on single neurons' nonstationary coarse spiking rates and local network activation, explained most of the fine synchrony in both seizure types. Our findings indicate that fine neuronal ensemble synchrony occurs mostly during SWC, not gamma-band, seizures, and primarily during the initial phase of SWC spikes. Furthermore, these fine synchrony events result mostly from transient increases in overall neuronal network spiking rates, rather than changes in precise spiking correlations between specific pairs of neurons.
- Additive gene-environment effects on hippocampal structure in healthy humans. [Journal Article]
- J Neurosci 2014 Jul 23; 34(30):9917-26.
Hippocampal volume loss has been related to chronic stress as well as genetic factors. Although genetic and environmental variables affecting hippocampal volume have extensively been studied and related to mental illness, limited evidence is available with respect to G × E interactions on hippocampal volume. The present MRI study investigated interaction effects on hippocampal volume between three well-studied functional genetic variants (COMT Val158Met, BDNF Val66Met, 5-HTTLPR) associated with hippocampal volume and a measure of environmental adversity (life events questionnaire) in a large sample of healthy humans (n = 153). All three variants showed significant interactions with environmental adversity with respect to hippocampal volume. Observed effects were additive by nature and driven by both recent as well as early life events. A consecutive analysis of hippocampal subfields revealed a spatially distinct profile for each genetic variant suggesting a specific role of 5-HTTLPR for the subiculum, BDNF Val66Met for CA4/dentate gyrus, and COMT Val158Met for CA2/3 volume changes. The present study underscores the importance of G × E interactions as determinants of hippocampal volume, which is crucial for the neurobiological understanding of stress-related conditions, such as mood disorders or post-traumatic stress disorder (PTSD).