Flexible Solution Processable Black Phosphorus Based Optoelectronic Memristive Synapse for Neuromorphic Computing and Artificial Visual Perception Applications.

Mutations in the synaptic gene SHANK3 lead to a neurodevelopmental disorder known as Phelan-McDermid syndrome (PMS). PMS is a relatively common monogenic and highly penetrant cause of autism spectrum disorder (ASD) and intellectual disability (ID), and frequently presents with attention deficits. The underlying neurobiology of PMS is not fully known and pharmacological treatments for core symptoms do not exist. Here, we report the production and characterization of a Shank3-deficient rat model of PMS, with a genetic alteration similar to a human SHANK3 mutation. We show that Shank3-deficient rats exhibit impaired long-term social recognition memory and attention, and reduced synaptic plasticity in the hippocampal-medial prefrontal cortex pathway. These deficits were attenuated with oxytocin treatment. The effect of oxytocin on reversing non-social attention deficits is a particularly novel finding, and the results implicate an oxytocinergic contribution in this genetically defined subtype of ASD and ID, suggesting an individualized therapeutic approach for PMS.DOI: http://dx.doi.org/10.7554/eLife.18904.001

The influence of circadian rhythms on memory has long been studied; however, the molecular prerequisites for their interaction remain elusive. The hippocampus, which is a region of the brain important for long-term memory formation and temporary maintenance, shows circadian rhythmicity in pathways central to the memory-consolidation process. As neuronal plasticity is the translation of numerous inputs, illuminating the direct molecular links between circadian rhythms and memory consolidation remains a daunting task. However, the elucidation of how clock genes contribute to synaptic plasticity could provide such a link. Furthermore, the idea that memory training could actually function as a zeitgeber for hippocampal neurons is worth consideration, based on our knowledge of the entrainment of the circadian clock system. The integration of many inputs in the hippocampus affects memory consolidation at both the cellular and the systems level, leaving the molecular connections between circadian rhythmicity and memory relatively obscure but ripe for investigation.

The hippocampal protein kinase C (PKC) family is involved in the early events of consolidation of long-term potentiation (LTP) and long-term memory (LTM). Results so far are indecisive about which PKC isoform is involved and as to whether any of them plays a role in short-term memory (STM) processes, which have recently been shown to be separate from those of LTM in the hippocampus-dependent one-trial step-down inhibitory avoidance task. To measure the effect of two PKC inhibitors, one (Gö 6976) selective to the calcium-dependent isoforms alpha and beta I, and the other (Gö 7874) unspecific as to PKC isoforms on the formation and retrieval of STM and LTM of one-trial inhibitory avoidance. Rats bilaterally implanted with cannulae in the CA1 region of the dorsal hippocampus were trained in one-trial step-down inhibitory avoidance. The effect of these two drugs on STM and LTM formation was investigated as follows. Animals were infused 10 min before or 50, 110, or 170 min after inhibitory avoidance training with a vehicle (2% dimethylsulfoxide in saline), or with Gö 6976 (0.92 nM or 4.6 nM) or Gö 7874 (1.96 nM or 8 nM) dissolved in the vehicle. Infusion volume was 0.5 microliter in all cases. Animals were tested 1.5 h and 3 h after training for STM and at 24 h for LTM. In order to study the effects of these compounds on retrieval, they were infused into the hippocampus 10 min prior to STM testing at 3 h (see above) or 10 min before LTM testing at 24 h. In addition, the effect of Gö 6976 and Gö 7874 was studied on general activity measured in an open field, and on performance in an elevated plus maze. STM was suppressed by 4.6 nM Gö 6976 given 10 min before or 50 min after training. LTM was cancelled by the higher dose of the two compounds given 10 min before, or 50 min or 110 min after training. None of the two compounds infused 170 min post-training affected the retrieval of STM measured 10 min later. However, both compounds given 10 min before testing inhibited the retrieval of LTM measured at 24 h. This effect cannot be attributed to influences on locomotor activity or anxiety levels, since the drugs had no effect on performance in the open field but were mildly "anxiogenic" (pro-conflict) and reduced the number of entries into open and closed arms and rearings. LTM consolidation requires in part alpha- and/or beta 1-PKC and in part other PKC isoforms. STM formation requires instead only alpha and/or beta I-PKC and during a more limited period of time. In addition, PKC appears not to be necessary for the retrieval of STM, but is crucial for the retrieval of LTM. These findings further point to a biochemical separation of STM and LTM, as ascertained in numerous previous studies.

Estrogenic and androgenic steroids can be synthesised in the brain and rapidly modulate synaptic transmission and plasticity through direct interaction with membrane receptors for estrogens (ERs) and androgens (ARs). We used whole cell patch clamp recordings in brainstem slices of male rats to explore the influence of ER and AR activation and local synthesis of 17β-estradiol (E2) and 5α-dihydrotestosterone (DHT) on the long-term synaptic changes induced in the neurons of the medial vestibular nucleus (MVN). Long-term depression (LTD) and long-term potentiation (LTP) caused by different patterns of high frequency stimulation (HFS) of the primary vestibular afferents were assayed under the blockade of ARs and ERs or in the presence of inhibitors for enzymes synthesizing DHT (5α-reductase) and E2 (P450-aromatase) from testosterone (T). We found that LTD is mediated by interaction of locally produced androgens with ARs and LTP by interaction of locally synthesized E2 with ERs. In fact, the AR block with flutamide prevented LTD while did not affect LTP, and the blockade of ERs with ICI 182,780 abolished LTP without influencing LTD. Moreover, the block of P450-aromatase with letrozole not only prevented the LTP induction, but inverted LTP into LTD. This LTD is likely due to the local activation of androgens, since it was abolished under blockade of ARs. Conversely, LTD was still induced in the presence of finasteride the inhibitor of 5α-reductase demonstrating that T is able to activate ARs and induce LTD even when DHT is not synthesized. This study demonstrates a key and opposite role of sex neurosteroids in the long-term synaptic changes of the MVN with a specific role of T-DHT for LTD and of E2 for LTP. Moreover, it suggests that different stimulation patterns can lead to LTD or LTP by specifically activating the enzymes involved in the synthesis of androgenic or estrogenic neurosteroids.

The purpose of this study was to investigate participants’ long- and short-term memory performance under different light environments and time situations. Forty-two participants were recruited. The participants’ short- and long-term memory capacities were evaluated under the three lighting conditions (300 lx, 600 lx and 800 lx) and at two times (morning and afternoon). The results showed that different illuminance levels significantly affected participants’ short- and long-term memory capacities. In the 2-back test, participants performed better in the 800 lx environment. For the concept map test, results reported that better memory capacity was found in the 600 lx environment. Regarding the time factor, the time effect significantly affected long-term memory. Participants performed significantly better in the morning than in the afternoon across all tasks. The final results were obtained using the response surface method. The 800 lx illumination combination in the morning was optimal for both short-term and long-term memory performance. In conclusion, the main finding is that participants’ long-term and short-term memory capacity varied depending on the lighting conditions, with illuminance significantly affecting both short-term and long-term memory. The results might have implications for future lighting research as well as lighting design for memory capacity work needs.

Epigenetic regulation of cellular identity and function is at least partly achieved through changes in covalent modifications on DNA and histones. Much progress has been made in recent years to understand how these covalent modifications affect cell identity and function. Despite the advances, whether and how epigenetic factors contribute to memory formation is still poorly understood. In this review, we discuss recent progress in elucidating epigenetic mechanisms of learning and memory, primarily at the DNA level, and look ahead to discuss their potential implications in reward memory and development of drug addiction.

Storage or processing of information underlies a mechanism able to change the efficacy of certain synapses depending on its activity. Long-term potentiation (LTP) and long-term depression (LTD) are two types of experimentally induced activity dependent change in synaptic efficacy (plasticity). The aim of this study was to determine the subtype specific involvement of group I metabotropic glutamate receptors (mGlus) in both forms of synaptic plasticity, namely LTP and LTD. The mGlu activation underlying pathological processes was also investigated. For all investigations, rats were chronically implanted with recording and stimulating electrodes to enable measurement of evoked potentials from medial perforant path -- dentate gyrus granule cell synapses. An injection cannula was inserted into the ipsilateral cerebral ventricle to enable drug application. Experiments were begun 10d subsequent to the implantation procedure. Histological investigations of hippocampal tissue was used to determine possible changes in cell viability after the induction of chemical LTD. Robust LTP which lasted for over 25h was generated using 200Hz tetanisation (HFT), whereas robust LTD was induced either by 1Hz low-frequency stimulation (LFS) or by pharmacological mGlu activation. The potent mGlu5 receptor agonist MPEP (2-methyl-6-(phenylethynyl)pyridine), applied in concentrations which did not affect basal synaptic transmission, dose-dependently impaired the induction and expression of LTP. Application of MPEP 5 min after tetanisation inhibited late LTP (> 24h). Injections of the potent mGlu1 agonist LY367385 ((S)-(+)-α-Amino-4-carboxy-2-methylbenzenacetic acid), in the concentrations investigated, did not effect basal synaptic transmission. In contrast, a dose- dependent impairment of LTP expression was observed. The lowest concentration used, had no effect on LTP induction, whereas higher concentrations reduced both LTP induction and expression. In contrast to MPEP application, the injection of LY367385 5min after LTP induction did not effect LTP expression. The results strongly implicate an involvement of mGlu1 in LTP induction, whereas the group I mGlu subtype 5 seems to be more involved in LTP expression. Investigating the subtype specific group I mGlu involvement in LTD afford differential results. Whereas LFS-induced LTD strongly required mGlu1 activation during LFS, chemical LTD is induced by activation of mGlu5. Induction of chemical LTD with the group I mGlu receptor agonist, (RS)-3,5-Dihydroxyphenylglycine (DHPG) occluded subsequent induction of LFS- induced LTD. Application of LFS following selective pharmacological activation of mGlu5 by (RS)-2-Chloro-5-hydroxyphenylglycine (CHPG) led to de-depression. Further analysis revealed that concurrent induction of chemically-induced and LFS-induced LTD led to an increase of intracellular calcium sufficient for the induction of LTP by LFS. Whereas LFS-induced LTD required mGlu1 activation during LFS, activation of mGlu5-mediated chemical LTD did not influence responses during LFS. In a next step, it was possible to induce stable LTD by application of the potent group III mGlu agonist AP4 (L-(+)-2-Amino-4-phosphonobutyric acid). The persistent LTD induced by the group I mGlu receptor agonist, DHPG, or the group III mGlu receptor agonist, AP4 were compared. Application of the protein synthesis inhibitor Anisomycin 2h prior to DHPG-injection inhibited the expression of LTD from 6h following DHPG injection. In contrast, Anisomycin did not affect LTD induced by AP4. A paired pulse paradigm determined that AP4-LTD is presynaptic whereas DHPG-LTD has both pre-and postsynaptic components. Histological evaluation at either 4h or 7d following AP4-injection showed that AP4-mediated LTD was ... [abstract truncated]

Hippocampal synaptic plasticity, in the form of long-term potentiation (LTP) and long-term depression (LTD), enables spatial memory formation, whereby LTP and LTD are likely to contribute different elements to the resulting spatial representation. Dopamine, released from the ventral tegmental area particularly under conditions of reward, acts on the hippocampus, and may specifically influence the encoding of information into long-term memory. The dentate gyrus (DG), as the "gateway" to the hippocampus is likely to play an important role in this process. D1/D5 dopamine receptors are importantly involved in the regulation of synaptic plasticity thresholds in the CA1 region of the hippocampus and determine the direction of change in synaptic strength that occurs during novel spatial learning. Here, we explored whether D1/D5-receptors influence LTD that is induced in the DG following patterned afferent stimulation of the perforant path of freely behaving adult rats, or influence LTD that occurs in association with spatial learning. We found that LTD that is induced by afferent stimulation, and LTD that is facilitated by learning about novel landmark configurations, were both prevented by D1/D5-receptor antagonism, whereas agonist activation of the D1/D5-receptor had no effect on basal tonus or short-term depression. Other studies have reported that in the DG, D1/D5-receptor agonism or antagonism do not affect LTP, but agonism prevents depotentiation. These findings suggest that the dopaminergic system, acting via D1/D5-receptors, influences information gating by the DG and modulates the direction of change in synaptic strength that underlies information storage in this hippocampal substructure. Information encoded by robust forms of LTD is especially dependent on D1/D5-receptor activation. Thus, dopamine acting on D1/D5-receptors is likely to support specific experience-dependent encoding, and may influence the content of hippocampal representations of experience.

Cannabinoids, the active constituents of marijuana, are known to impair learning and memory. Receptors for cannabinoids are highly expressed in the hippocampus, a brain region that is believed to play an important role in certain forms of learning and memory. To investigate the possible contribution of cannabinoid receptor-mediated deficits in hippocampal function to the learning and memory impairments produced by marijuana, we studied the effects of cannabinoid receptor activation on two models of learning and memory, long-term potentiation (LTP) and long-term depression (LTD), in hippocampal slices. Although LTP and LTD of CA1 field potentials were blocked by cannabinoid receptor activation in the presence of Mg(2+), they could be induced after Mg(2+) was removed. Similarly, LTP and LTD of whole-cell EPSCs were unimpaired in the presence of cannabinoid receptor agonist when the postsynaptic membrane was depolarized during the LTP or LTD induction protocol. Cannabinoid receptor activation also reduced EPSCs and enhanced paired-pulse facilitation, while having no effect on the amplitude of spontaneous miniature EPSCs. Finally, as with cannabinoid receptor activation, inhibition of LTP by adenosine receptor activation could be overcome by removal of Mg(2+) or depolarization of the postsynaptic membrane during tetanus. Our results indicate that cannabinoid receptor activation does not directly inhibit the molecular mechanisms responsible for long-term synaptic plasticity but instead impairs LTP and LTD by reducing presynaptic neurotransmitter release to a level below that required to depolarize the postsynaptic membrane to relieve Mg(2+) blockade of NMDA receptors.

Age-related deficits in associative episodic memory have been widely reported, but recent research suggests that some of these deficits occur for highly specific but not gist representations. It remains undetermined whether older adults' deficits in specific associative episodic memory, observed in long-term memory, are also present in short-term memory. We used a continuous associative recognition task to address this question. Fifty young and 50 older adults studied face-scene pairs, with memory tests occurring in both short-term and long-term memory. Memory tests featured intact (old) pairs, related (similar) pairs, and unrelated (dissimilar) pairs. On short-term memory tests, older adults were less accurate in classifying related pairs, which was manifest by age-related reductions in the probability of retrieving specific memory to engage in recollection rejection. However, older adults were capable of remembering specific details in short-term memory for intact probes but were less likely to remember specific details in long-term memory. Finally, older adults were always as capable as younger adults of remembering gist details. Results suggest that older adults do at least partially encode specific representations in short-term memory, and their access to these specific representations is cue dependent-they can do so when there is a large correspondence between encoding and retrieval conditions but are less likely to engage in deeper elaboration at retrieval. This limits their ability to remember specific details of associations to suppress false recognitions in short-term memory and to engage in veridical recognition in long-term memory. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Ion-gel-based memory devices can effectively change their resistance states even at low voltages, owing to the rapid mobility of ions and the formation of an electric double layer. However, their volatile characteristics limit their use in nonvolatile memory and neuromorphic applications. In this paper, we report an ion-gel-based memristive device capable of both digital data storage and analog data processing through the incorporation of silver nanoparticles (AgNPs). The memristive device exhibited reliable resistive switching behavior, characterized by forming-free and a butterfly shaped bipolar resistive switching (BRS) profile. Notably, the ion-gel-based memristive device with AgNPs demonstrated excellent data retention for over 105 s even at 85 °C, attributed to the charge storage stability provided by Ag+-based ion pairing. In addition to memory functionality, the device successfully emulated various synaptic behaviors, including long-term potentiation (LTP), long-term depression (LTD), and the transition from short-term memory (STM) to long-term memory (LTM). Furthermore, it achieved clear digit classification results in learning and inference tasks, with a recognition accuracy of up to 96.4%.

A robust high-performance electronic synapse based on epitaxial ferroelectric Hf0.5Zr0.5O2 films with uniform polarization and high Curie temperature

Differential roles of NR2A and NR2B-containing NMDA receptors in LTP and LTD in the CA1 region of two-week old rat hippocampus

1. Extracellular bath application of the selective Ca2+/calmodulin-dependent kinase II (CaMKII) inhibitor KN-62 to hippocampal slices in vitro blocked the induction of long-term depression (LTD) by low-frequency Schaffer collateral stimulation (1 Hz/15 min) of the same concentration as has been shown previously to prevent induction of long-term potentiation (LTP) at these synapses. 2. In contrast, postsynaptic intracellular infusion of KN-62 into single CA1 pyramidal neurons did not prevent induction of LTD, although it was quite effective in blocking LTP. 3. We conclude that there is a presynaptic CaMKII that must be activated to induce LTD, whereas postsynaptic CaMKII stimulation is needed to evoke LTP. 4. Bath application of KN-62 also blocked depotentiation by low-frequency stimuli of previously induced LTP, suggesting that induction of depotentiation and de novo LTD may require the same CaMKII-dependent mechanisms.

One of the promising future ways of computing is using principles similar to the human brain work mechanism. Neuromorphic photonics makes it possible to create computational elements with properties similar to the principles of the biological synapse. Neuromorphic computers can overcome the von Neumann bottleneck fundamental limitation of existing computing systems. In a current study, we demonstrate a neuromorphic properties, observing on photoconductive structures based on nanocrystalline ZnO, WO3, In2O3 triggered by presynaptic light spikes with the 405nm wavelength. Photoconductive structures based on ZnO, WO3, In2O3 were deposited as a 100–200 nm thick film on the surface of the chip. Excitatory post-synaptic current value was measured for different excitation pulse durations. The excitatory post-synaptic current caused by a pair of presynaptic light spikes was studied for different delay times between pulses. The ability of these structures to act as biological synapses like high-pass temporal filtering function was demonstrated by measuring post-synaptic current when exposed to a series of 30 consecutive presynaptic light spikes. Our photoconductive semiconductor structures have two different relaxation mechanisms. Due to this, the structures possess short-term and long-term photoconductivity memory. To demonstrate the ability of our samples possesses long-term memory, we studied the semiconductor photoconductivity relaxation values after light exposure during 500 seconds. The memory level after light exposure were stored over an hour. The studied photoconductive structures showed the presence of a spike reaction properties, the effect of amplitude and frequency filtering, short-term and long-term memory, and they are looking promising for use as elements of neuromorphic photonics.