Explore the vast range of titles available.

Background Transcranial direct current stimulation (tDCS) is capable of eliciting changes in cortical neuroplasticity. Increasing duration or repetition of tDCS during the after-effects of a first stimulation has been hypothesized to enhance efficacy. Computational models suggest sequential stimulation patterns with changing polarities to further enhance effects. Lasting tDCS effects on neural plasticity are of great importance for clinical applications. Objective The study systematically examined the influence of different tDCS paradigms on long term potentiation (LTP)-like plasticity in humans, focusing on stimulation duration, repetition frequency and sequential combinations of changing polarities as the underlying characteristics. Methods Amplitude changes of motor evoked potentials (MEP) were measured in response to paired associative stimulation (PAS) 6 h after application of different tDCS protocols. In total, 36 healthy participants completed the study, randomised into three groups with different stimulation protocols (N = 12 each). Results tDCS was able to display lasting modulatory effects on the inducibility of LTP-like plasticity in the human motor cortex 6 h after stimulation. TDCS with the anode on primary motor cortex significantly increased MEP amplitudes following PAS induction. Further analyses highlighted single stimulation block duration to be of higher importance than repetitive protocols for efficacy of effects. Conclusions tDCS is capable of inducing lasting changes in the brain’s capability to interact with future stimuli. Especially, effects on the inducibility of LTP-like plasticity might only be detectable with specific tests such as PAS and might otherwise be overlooked. Refined tDCS protocols should focus on higher current and duration of single stimulations instead of implementing complex repetitive schedules.

Background Subjective cognitive decline (SCD) is a self-perceived cognitive complaint in the absence of objective impairment, representing an at-risk state along the continuum of cognitive aging. High-frequency repetitive transcranial magnetic stimulation (rTMS) over the left dorsolateral prefrontal cortex (L-DLPFC) has shown cognitive benefits in Alzheimer’s disease (AD), yet its effects on cognitive functions in SCD remain largely unexplored. Objective To evaluate the effects of 10-Hz rTMS over the L-DLPFC in individuals with SCD on cognitive functions and long-term potentiation (LTP)-like plasticity, indexed by changes in motor evoked potential (MEP) following intermittent theta burst stimulation, and examine the relationship between brain plasticity and cognitive outcomes. Methods In this randomized, sham-controlled trial, 42 individuals with SCD received 20 sessions of either active or sham 10-Hz rTMS ( n  = 21 per group) over four weeks. The primary outcome was delayed episodic memory, evaluated using the Auditory Verbal Learning Test-Huashan version (AVLT-H). Secondary outcomes included additional cognitive measures and MEP amplitudes at baseline and at 5 (T 5 ), 10 (T 10 ), and 30 (T 30 ) minutes post-intervention. Results The rTMS group exhibited significant improvements in both delayed episodic memory (AVLT-N5) and MEP amplitudes at T 5 and T 10 following the intervention, whereas such changes were not observed in the sham group. Moreover, increased MEP amplitude at T 10 was positively correlated with improved AVLT-N5 performance. Conclusions These findings provide the first evidence for enhanced delayed episodic memory and LTP-like plasticity in individuals with SCD following 10-Hz rTMS over the L-DLPFC, suggesting a potential role of LTP-like plasticity in elucidating the neurophysiological correlates of cognitive improvements for SCD. Trial registration The study design and analysis plan were preregistered on September 7th, 2023 at Chinese Clinical Trial Registry (No. ChiCTR2300075517).

We used electroencephalography (EEG) together with psychopharmacological stimulation to investigate the role of dopamine in neural oscillations during working memory (WM). Following a within-subjects design, healthy humans either received the dopamine precursor l-Dopa (150mg) or a placebo before they performed a Sternberg WM paradigm. Here, sequences of sample images had to be memorized for a delay of 5s in three different load conditions (two, four or six items). On the next day, long-term memory (LTM) for the images was tested. Behaviorally, l-Dopa improved WM and LTM performance as a function of WM load. More precisely, there was a specific drug effect in the four-load condition with faster reaction times to the probe in the WM task and higher corrected hit-rates in the LTM task. During the maintenance period, there was a linear and quadratic effect of WM load on power in the high theta (5–8Hz) and alpha (9–14Hz) frequency range at frontal sensors. Importantly, a drug by load interaction – mimicking the behavioral results – was found only in low theta power (2–4Hz). As such, our results indicate a specific link between prefrontal low theta oscillations, dopaminergic neuromodulation during WM and subsequent LTM performance. •Dopaminergic stimulation improved WM and LTM performance as a function of WM load.•This behavioral effect was accompanied by increased power in low theta (2–4Hz).•High theta (5–8Hz) and alpha power (9–14Hz) were modulated by WM load but not drug.•Together, our data indicate functional interactions between WM and LTM systems.•Low vs. high theta and alpha oscillations serve different roles in WM maintenance.

Long-term potentiation (LTP) of synaptic efficacy is considered a fundamental mechanism of learning and memory. At the cellular level a large body of evidence demonstrated that the major neuromodulatory neurotransmitters dopamine (DA), norepinephrine (NE), and acetylcholine (ACh) influence LTP magnitude. Noninvasive brain stimulation protocols provide the opportunity to study LTP-like plasticity at the systems level of human cortex. Here we applied paired associative stimulation (PAS) to induce LTP-like plasticity in the primary motor cortex of eight healthy subjects. In a double-blind, randomized, placebo-controlled, crossover design, the acute effects of a single oral dose of the neuromodulatory drugs cabergoline (DA agonist), haloperidol (DA antagonist), methylphenidate (indirect NE agonist), prazosine (NE antagonist), tacrine (ACh agonist), and biperiden (ACh antagonist) on PAS-induced LTP-like plasticity were examined. The antagonists haloperidol, prazosine, and biperiden depressed significantly the PAS-induced LTP-like plasticity observed under placebo, whereas the agonists cabergoline, methylphenidate, and tacrine had no effect. Findings demonstrate that antagonists in major neuromodulatory neurotransmitter systems suppress LTP-like plasticity at the systems level of human cortex, in accord with evidence of their modulating action of LTP at the cellular level. This provides further supportive evidence for the known detrimental effects of these drugs on LTP-dependent mechanisms such as learning and memory.

Mental strength and history of winning play an important role in the determination of social dominance. However, the neural circuits mediating these intrinsic and extrinsic factors have remained unclear. Working in mice, we identified a dorsomedial prefrontal cortex (dmPFC) neural population showing “effort”-related firing during moment-to-moment competition in the dominance tube test. Activation or inhibition of the dmPFC induces instant winning or losing, respectively. In vivo optogenetic-based long-term potentiation and depression experiments establish that the mediodorsal thalamic input to the dmPFC mediates long-lasting changes in the social dominance status that are affected by history of winning. The same neural circuit also underlies transfer of dominance between different social contests. These results provide a framework for understanding the circuit basis of adaptive and pathological social behaviors.

Background Postsynaptic density (PSD)-95-like membrane-associated guanylate kinases (PSD-MAGUKs) are scaffold proteins in PSDs that cluster signaling molecules near NMDA receptors. PSD-MAGUKs share a common domain structure, including three PDZ (PDZ1/2/3) domains in their N-terminus. While multiple domains enable the PSD-MAGUKs to bind various ligands, the contribution of each PDZ domain to synaptic organization and function is not fully understood. Here, we focused on the PDZ1/2 domains of PSD-95 that bind NMDA-type receptors, and studied the specific roles of the ligand binding of these domains in the assembly of PSD proteins, synaptic properties of hippocampal neurons, and behavior, using ligand binding-deficient PSD-95 cDNA knockin (KI) mice. Results The KI mice showed decreased accumulation of mutant PSD-95, PSD-93 and AMPA receptor subunits in the PSD fraction of the hippocampus. In the hippocampal CA1 region of young KI mice, basal synaptic efficacy was reduced and long-term potentiation (LTP) was enhanced with intact long-term depression. In adult KI mice, there was no significant change in the magnitude of LTP in CA1, but robustly enhanced LTP was induced at the medial perforant path-dentate gyrus synapses, suggesting that PSD-95 has an age- and subregion-dependent role. In a battery of behavioral tests, KI mice showed markedly abnormal anxiety-like behavior, impaired spatial reference and working memory, and impaired remote memory and pattern separation in fear conditioning test. Conclusions These findings reveal that PSD-95 including its ligand binding of the PDZ1/2 domains controls the synaptic clustering of PSD-MAGUKs and AMPA receptors, which may have an essential role in regulating hippocampal synaptic transmission, plasticity, and hippocampus-dependent behavior.

Learning is primarily mediated by activity-dependent modifications of synaptic strength within neuronal circuits. We discovered that place fields in hippocampal area CA1 are produced by a synaptic potentiation notably different from Hebbian plasticity. Place fields could be produced in vivo in a single trial by potentiation of input that arrived seconds before and after complex spiking. The potentiated synaptic input was not initially coincident with action potentials or depolarization. This rule, named behavioral time scale synaptic plasticity, abruptly modifies inputs that were neither causal nor close in time to postsynaptic activation. In slices, five pairings of subthreshold presynaptic activity and calcium (Ca2+) plateau potentials produced a large potentiation with an asymmetric seconds-long time course. This plasticity efficiently stores entire behavioral sequences within synaptic weights to produce predictive place cell activity.

A rodent study using optogenetics to induce long-term potentiation and long-term depression provides a causal link between synaptic plasticity and memory. Memories made and unmade It has long been thought that the neural mechanisms underlying memories involve synaptic plasticity such as long-term potentiation (LTP) and long-term depression (LTD), but demonstrating a causal link between these synaptic processes and memory has been difficult. Now, Roberto Malinow and colleagues claim to have done just that in mice undergoing fear conditioning. The authors use optogenetics to isolate a specific fear memory circuit and then induce LTD or LTP within the circuit to remove or reinstate the memory. It has been proposed that memories are encoded by modification of synaptic strengths through cellular mechanisms such as long-term potentiation (LTP) and long-term depression (LTD) 1 . However, the causal link between these synaptic processes and memory has been difficult to demonstrate 2 . Here we show that fear conditioning 3 , 4 , 5 , 6 , 7 , 8 , a type of associative memory, can be inactivated and reactivated by LTD and LTP, respectively. We began by conditioning an animal to associate a foot shock with optogenetic stimulation of auditory inputs targeting the amygdala, a brain region known to be essential for fear conditioning 3 , 4 , 5 , 6 , 7 , 8 . Subsequent optogenetic delivery of LTD conditioning to the auditory input inactivates memory of the shock. Then subsequent optogenetic delivery of LTP conditioning to the auditory input reactivates memory of the shock. Thus, we have engineered inactivation and reactivation of a memory using LTD and LTP, supporting a causal link between these synaptic processes and memory.

It is assumed that synaptic strengthening and weakening balance throughout learning to avoid runaway potentiation and memory interference. However, energetic and informational considerations suggest that potentiation should occur primarily during wake, when animals learn, and depression should occur during sleep. We measured 6920 synapses in mouse motor and sensory cortices using three-dimensional electron microscopy. The axon-spine interface (ASI) decreased ~18% after sleep compared with wake. This decrease was proportional to ASI size, which is indicative of scaling. Scaling was selective, sparing synapses that were large and lacked recycling endosomes. Similar scaling occurred for spine head volume, suggesting a distinction between weaker, more plastic synapses (~80%) and stronger, more stable synapses. These results support the hypothesis that a core function of sleep is to renormalize overall synaptic strength increased by wake.

The modification of synaptic strength produced by long-term potentiation (LTP) is widely thought to underlie memory storage. Indeed, given that hippocampal pyramidal neurons have >10,000 independently modifiable synapses, the potential for information storage by synaptic modification is enormous. However, recent work suggests that CREB-mediated global changes in neuronal excitability also play a critical role in memory formation. Because these global changes have a modest capacity for information storage compared with that of synaptic plasticity, their importance for memory function has been unclear. Here we review the newly emerging evidence for CREB-dependent control of excitability and discuss two possible mechanisms. First, the CREB-dependent transient change in neuronal excitability performs a memory-allocation function ensuring that memory is stored in ways that facilitate effective linking of events with temporal proximity (hours). Second, these changes may promote cell-assembly formation during the memory-consolidation phase. It has been unclear whether such global excitability changes and local synaptic mechanisms are complementary. Here we argue that the two mechanisms can work together to promote useful memory function.