Associative Memory Cells Research Articles

Associative memory cells of encoding fear signals and anxiety are recruited by neuroligin-3-mediated synapse formation

Acute severe stress may induce fear memory and anxiety. Their mechanisms are expectedly revealed to explore therapeutic strategies. We have investigated the recruitment of associative memory cells that encode stress signals to cause fear memory and anxiety by multidisciplinary approaches. In addition to fear memory and anxiety, the social stress by the resident/intruder paradigm leads to synapse interconnections between somatosensory S1-Tr and auditory cortical neurons in intruder mice. These S1-Tr cortical neurons become to receive convergent synapse innervations newly from the auditory cortex and innately from the thalamus as well as encode the stress signals including battle sound and somatic pain, i.e., associative memory neurons. Neuroligin-3 mRNA knockdown in the S1-Tr cortex precludes the recruitment of associative memory neurons and the onset of fear memory and anxiety. The stress-induced recruitment of associative memory cells in sensory cortices for stress-relevant fear memory and anxiety is based on neuroligin-3-mediated new synapse formation.

Neuroligin-3-Mediated Synapse Formation Strengthens Interactions between Hippocampus and Barrel Cortex in Associative Memory.

Memory traces are believed to be broadly allocated in cerebral cortices and the hippocampus. Mutual synapse innervations among these brain areas are presumably formed in associative memory. In the present study, we have used neuronal tracing by pAAV-carried fluorescent proteins and neuroligin-3 mRNA knockdown by shRNAs to examine the role of neuroligin-3-mediated synapse formation in the interconnection between primary associative memory cells in the sensory cortices and secondary associative memory cells in the hippocampus during the acquisition and memory of associated signals. Our studies show that mutual synapse innervations between the barrel cortex and the hippocampal CA3 region emerge and are upregulated after the memories of associated whisker and odor signals come into view. These synapse interconnections are downregulated by a knockdown of neuroligin-3-mediated synapse linkages. New synapse interconnections and the strengthening of these interconnections appear to endorse the belief in an interaction between the hippocampus and sensory cortices for memory consolidation.

Associative memory neurons of encoding multi-modal signals are recruited by neuroligin-3-mediated new synapse formation

The joint storage and reciprocal retrieval of learnt associated signals are presumably encoded by associative memory cells. In the accumulation and enrichment of memory contents in lifespan, a signal often becomes a core signal associatively shared for other signals. One specific group of associative memory neurons that encode this core signal likely interconnects multiple groups of associative memory neurons that encode these other signals for their joint storage and reciprocal retrieval. We have examined this hypothesis in a mouse model of associative learning by pairing the whisker tactile signal sequentially with the olfactory signal, the gustatory signal, and the tail-heating signal. Mice experienced this associative learning show the whisker fluctuation induced by olfactory, gustatory, and tail-heating signals, or the other way around, that is, memories to multi-modal associated signals featured by their reciprocal retrievals. Barrel cortical neurons in these mice become able to encode olfactory, gustatory, and tail-heating signals alongside the whisker signal. Barrel cortical neurons interconnect piriform, S1-Tr, and gustatory cortical neurons. With the barrel cortex as the hub, the indirect activation occurs among piriform, gustatory, and S1-Tr cortices for the second-order associative memory. These associative memory neurons recruited to encode multi-modal signals in the barrel cortex for associative memory are downregulated by neuroligin-3 knockdown. Thus, associative memory neurons can be recruited as the core cellular substrate to memorize multiple associated signals for the first-order and the second-order of associative memories by neuroligin-3-mediated synapse formation, which constitutes neuronal substrates of cognitive activities in the field of memoriology.

Associative memory neurons of encoding multi-modal signals are recruited by neuroligin-3-mediated new synapse formation.

The joint storage and reciprocal retrieval of learnt associated signals are presumably encoded by associative memory cells. In the accumulation and enrichment of memory contents in lifespan, a signal often becomes a core signal associatively shared for other signals. One specific group of associative memory neurons that encode this core signal likely interconnects multiple groups of associative memory neurons that encode these other signals for their joint storage and reciprocal retrieval. We have examined this hypothesis in a mouse model of associative learning by pairing the whisker tactile signal sequentially with the olfactory signal, the gustatory signal, and the tail-heating signal. Mice experienced this associative learning show the whisker fluctuation induced by olfactory, gustatory, and tail-heating signals, or the other way around, that is, memories to multi-modal associated signals featured by their reciprocal retrievals. Barrel cortical neurons in these mice become able to encode olfactory, gustatory, and tail-heating signals alongside the whisker signal. Barrel cortical neurons interconnect piriform, S1-Tr, and gustatory cortical neurons. With the barrel cortex as the hub, the indirect activation occurs among piriform, gustatory, and S1-Tr cortices for the second-order associative memory. These associative memory neurons recruited to encode multi-modal signals in the barrel cortex for associative memory are downregulated by neuroligin-3 knockdown. Thus, associative memory neurons can be recruited as the core cellular substrate to memorize multiple associated signals for the first-order and the second-order of associative memories by neuroligin-3-mediated synapse formation, which constitutes neuronal substrates of cognitive activities in the field of memoriology.

The Framework and Memristive Circuit Design for Multisensory Mutual Associative Memory Networks.

In this work, we propose a multisensory mutual associative memory networks framework and memristive circuit to mimic the ability of the biological brain to make associations of information received simultaneously. The circuit inspired by neural mechanisms of associative memory cells mainly consists of three modules: 1) the storage neurons module, which encodes external multimodal information into the firing rate of spikes; 2) the synapse module, which uses the nonvolatility memristor to achieve weight adjustment and associative learning; and 3) the retrieval neuron module, which feeds the retrieval signal output from each sensory pathway to other sensory pathways, so that achieve mutual association and retrieval between multiple modalities. Different from other one-to-one or many-to-one unidirectional associative memory work, this circuit achieves bidirectional association from multiple modalities to multiple modalities. In addition, we simulate the acquisition, extinction, recovery, transmission, and consolidation properties of associative memory. The circuit is applied to cross-modal association of image and audio recognition results, and episodic memory is simulated, where multiple images in a scene are intramodal associated. With power and area analysis, the circuit is validated as hardware-friendly. Further research to extend this work into large-scale associative memory networks, combined with visual-auditory-tactile-gustatory sensory sensors, is promising for application in intelligent robotic platforms to facilitate the development of neuromorphic systems and brain-like intelligence.

A novel brain-inspired hierarchical perception-association circuit based on memristor arrays

In the brain, primary sensory cells can efficiently perceive multimodal stimuli, and then associative memory cells perform an advanced bidirectional associative memory function with perceived information. Here, a brain-inspired hierarchical perception-association circuit based on memristor arrays is proposed. Firstly, a memristive reservoir computing circuit is designed to simulate a low-level perceptual function, which mainly comprises dynamic analog reservoirs, memristor arrays, and analog integrators, enabling efficient spatio-temporal information processing. Secondly, a spiking bidirectional associative memory memristive circuit, as the core of the whole circuit, is proposed to mimic a high-level associative function, which mainly consists of memristor arrays, current amplifiers, and leaky integrate-and-fire neuron circuits, implementing multimodal associative learning. The simulation results in LTspice show that the modified neuron circuit exhibits 66× improvement in energy efficiency, and the proposed circuit can precisely perform the letter association and vision–audio association tasks in a spiking fashion with an average firing energy consumption of 230 pJ/spike, which has a great potential to be embedded in mobile robotic platforms.

Will computing in memory become a new dawn of associative processors?

Computer architecture faces an enormous challenge in recent years: while the demand for performance is constantly growing, the performance improvement of general-purpose CPU has almost stalled. Among the reasons are memory and power walls, due to which data transfer increasingly dominates computing. By significantly reducing data transfer, data-centric (or in-memory) computing promises to alleviate the memory and power walls. Associative processor is a non von Neumann computer invented in the 1960s but effectively cast aside until recently. It computes using associative memory in a perfect induction like fashion, using associative memory cells for both data storage and processing. Associative processor can be implemented using conventional CMOS as well as emerging memories. We show that associative processor can outperform state-of-the-art computing platforms by up to almost two orders of magnitude in a variety of data-intensive workloads.

Multi-Layered QCA Content-Addressable Memory Cell Using Low-Power Electronic Interaction for AI-Based Data Learning and Retrieval in Quantum Computing Environment.

In this study, we propose a quantum structure of an associative memory cell for effective data learning based on artificial intelligence. For effective learning of related data, content-based retrieval and storage rather than memory address is essential. A content-addressable memory (CAM), which is an efficient memory cell structure for this purpose, in a quantum computing environment, is designed based on quantum-dot cellular automata (QCA). A CAM cell is composed of a memory unit that stores information, a match unit that performs a search, and a structure, using an XOR gate or an XNOR gate in the match unit, that shows good performance. In this study, we designed an XNOR gate with a multilayer structure based on electron interactions and proposed a QCA-based CAM cell using it. The area and time efficiency are verified through a simulation using QCADesigner, and the quantum cost of the proposed XOR gate and CAM cell were reduced by at least 70% and 15%, respectively, when compared to the latest research. In addition, we physically proved the potential energy owing to the interaction between the electrons inside the QCA cell. We also proposed an additional CAM circuit targeting the reduction in energy dissipation that overcomes the best available designs. The simulation and calculation of power dissipation are performed by QCADesigner-E and it is confirmed that more than 27% is reduced.

Expression of GABAergic and glutamatergic neurons after olfactory stimulation in the mouse piriform cortex during postnatal development

Introduction. The control of the survival and differentiation of immature neurons in the piriform cortex of rodents, which can transform into GABAergic and/or glutamatergic neurons under the influence of olfactory stimuli, is an important factor for prevention of neurological dysfunction.
 The aim of the study was to assess the expression of GABAergic and glutamatergic neurons after olfactory stimulation (OS) in the mouse piriform cortex during postnatal development.
 Materials and methods. The study was carried out on CD1 male mice aged 2 (n = 20; group Р2), 21 (n = 20; group Р21) and 60 (n = 20; group Р60) days. The mice were presented with olfactory stimuli, and brain tissue was collected for immunohistochemical analysis 2 hours, 24 hours and 7 days later, to assess glutamic acid decarboxylase 67 (GAD67) and vesicular glutamate transporter 1 (VGlut1) expression.
 Results. OS in the group P2 animals increased VGlut1 expression in the first 2 hours after OS, followed by a return to baseline level by day 7, while GAD67 expression showed no significant changes. The animals in group P21 showed increased expression of VGlut1 and GAD67 two hours after OS, followed by a significant decrease. Expression of both molecules demonstrated a statistically significant increase in the group P60 animals 24 hours after OS, and remained at the same level on day 7 (GAD67) or returned to baseline levels (VGlut1).
 Conclusion. OS increases the number of GABAergic (GAD67+) и glutamatergic (VGlut1+) neurons in the piriform cortex (P60). The predominance of glutamatergic effects is a possible mechanism for associative memory cell recruitment.

MemCAM: A Hybrid Memristor-CMOS CAM Cell for On-Chip Caches

Non-volatile nanoscale memory devices (such as memristors) have promised to overcome the challenges of scalability and leakage currents of CMOS based memory devices. These novel memories can be fabricated in back-end-of-the-line of any CMOS process. Currently, a lot of research is focused on investigating the benefits of memristors for associative memories. These are Content-Addressable Memories (CAM) in which search based data access takes place. Searching for a particular bit in memristor is time consuming while search in CMOS CAM zone is efficient. To combine the speed and ease of search of CMOS memory and the scalability of memristor memory, we present a novel multibit hybrid CMOS-Memristor Associative Memory Cell. The benefits of such memory cells manifest in on-chip caches - the instruction and data cache, Branch Target Buffer, and Translation Lookaside Buffer. To exemplify the benefit of the cell further, we also simulate the MemCAM as the TLB of an ARM processor and obtained upto 50% decrease in miss rates of Data TLB and upto 93% in that of Instruction TLB. Average speedup of 1.16 was also achieved on various benchmark applications of PARCSEC and MiBench suites.

MiRNA-324/-133a essential for recruiting new synapse innervations and associative memory cells in coactivated sensory cortices.

After the integrative storage of associated signals, a signal induces the recollection of its associated signal, or the other way around. This associative memory is essential to associative thinking, logical reasoning, imagination and computation. In terms of cellular mechanisms underlying associative memory, new mutual synapse innervations are formed among those coactivated neurons, so that they are recruited to be associative memory cells or associative memory neurons. These associative memory cells receive new synapse innervations alongside innate synapse inputs and encode signals carried by these inputs. We proposed to examine microRNAs as initiative factors for recruiting new synapse innervations and associative memory cells. In a mouse model of associative memory characterized as the reciprocal retrieval of associated whisker and odor signals, barrel and piriform cortical neurons gain their ability to encode whisker and odorant signals based on the newly formed synapse innervations between these coactivated cortices besides innate synapse inputs. miRNA-324 and miRNA-133a are required for recruiting these new synapse innervations and associative memory cells as well as sufficient for facilitating their recruitments, but not for innate synapse inputs. Therefore, the coactivation of sensory cortices through microRNA as initiative factor to recruit new mutual synapse innervations and associative memory cells for associative memory.

Activity-Dependent Plasticity at Associative Memory Cells in the Prefrontal Cortex

In addition to structural and functional alternations of neurons during their recruitment to be associative memory cells, these associative memory cells undergo the functional plasticity in response to their activity, called as recruitment-relevant plasticity and activity-dependent plasticity, respectively (Associative Memory Cells: Basic Units of Memory Trace by Jin-Hui Wang 2019). Here, we report the features of activity-dependent plasticity at associative memory cells studied by two-photon cell imaging. After the learning of triple associated signals (pair-stimulations by odor, whisker tactile and tail warming-up), secondary associative memory cells in response to these signals are recruited in the prefrontal cortex. The portion of functional associative memory cells is upregulated by intensive activity in one of three synaptic inputs or their combinations. When whisker, odor or tail stimulus is given intensively, the activity levels of these associative memory cells show low-to-high or high-to-low in response to original cues, especially activity-dependent depression in response to homosynaptic signal and activity-dependent potentiation in response to heterosynaptic signal. When whisker, odor and tail stimulations are given simultaneously, these associative memory cells express activity-dependent potentiation in response to all these input signals. The upregulated activities of norepinephrine and serotonin in the central nervous system strengthen the recruitment, the functional strength and the activity-dependent plasticity of associative memory cell in response to homosynaptic and heterosynaptic signals. As activity-dependent plasticity at associative memory cells occurs immediately after their activation, our results may be due to a possibility that the new synapses formed on associative memory cells during associative learning can be upregulated and downregulated between active state and inactive state, in which their intensive activities and monoamine neurotransmitters are critical modulators. The results can explain activity-related memory strengthening and the role of the arousal system through norepinephrine and serotonin in memory.

Coactivations of barrel and piriform cortices induce their mutual synapse innervations and recruit associative memory cells

After associative learning, a signal induces the recall of its associated signal, or the other way around. This reciprocal retrieval of associated signals is essential for associative thinking and logical reasoning. For the cellular mechanism underlying this associative memory, we hypothesized that the formation of synapse innervations among coactivated sensory cortices and the recruitment of associative memory cells were involved in the integrative storage and reciprocal retrieval of associated signals. Our study indicated that the paired whisker and olfaction stimulations led to an odorant-induced whisker motion and a whisker-induced olfaction response, a reciprocal form of associative memory retrieval. In mice that showed the reciprocal retrieval of associated signals, their barrel and piriform cortical neurons became mutually innervated through their axon projection and new synapse formation. These piriform and barrel cortical neurons gained the ability to encode both whisker and olfaction signals based on synapse innervations from the innate input and the newly formed input. Therefore, the associated activation of sensory cortices by pairing input signals initiates their mutual synapse innervations, and the neurons innervated by new and innate synapses are recruited to be associative memory cells that encode these associated signals. Mutual synapse innervations among sensory cortices to recruit associative memory cells may compose the primary foundation for the integrative storage and reciprocal retrieval of associated signals. Our study also reveals that new synapses onto the neurons enable these neurons to encode memories to new specific signals.

Searching basic units in memory traces: associative memory cells.

The acquisition of associated signals is commonly seen in life. The integrative storage of these exogenous and endogenous signals is essential for cognition, emotion and behaviors. In terms of basic units of memory traces or engrams, associative memory cells are recruited in the brain during learning, cognition and emotional reactions. The recruitment and refinement of associative memory cells facilitate the retrieval of memory-relevant events and the learning of reorganized unitary signals that have been acquired. The recruitment of associative memory cells is fulfilled by generating mutual synapse innervations among them in coactivated brain regions. Their axons innervate downstream neurons convergently and divergently to recruit secondary associative memory cells. Mutual synapse innervations among associative memory cells confer the integrative storage and reciprocal retrieval of associated signals. Their convergent synapse innervations to secondary associative memory cells endorse integrative cognition. Their divergent innervations to secondary associative memory cells grant multiple applications of associated signals. Associative memory cells in memory traces are defined to be nerve cells that are able to encode multiple learned signals and receive synapse innervations carrying these signals. An impairment in the recruitment and refinement of associative memory cells will lead to the memory deficit associated with neurological diseases and psychological disorders. This review presents a comprehensive diagram for the recruitment and refinement of associative memory cells for memory-relevant events in a lifetime.

Secondary Associative Memory Cells and their Plasticity in the Prefrontal Cortex

Secondary Associative Memory Cells and their Plasticity in the Prefrontal Cortex

Cell-specific plasticity associated with integrative memory of triple sensory signals in the barrel cortex.

Neuronal plasticity occurs in associative memory. Associative memory cells are recruited for the integration and storage of associated signals. The coordinated refinements and interactions of associative memory cells including glutamatergic and GABAergic neurons remain elusive, which we have examined in a mouse model of associative learning. Paired olfaction, tail and whisker stimulations lead to odorant-induced and tail-induced whisker motions alongside whisker-induced whisker motion. In mice that show this cross-modal associative memory, barrel cortical glutamatergic and GABAergic neurons are recruited to encode the newly learned odor and tail signals alongside the innate whisker signal. These glutamatergic neurons are functionally upregulated, and GABAergic neurons are refined in a homeostatic manner. The mutual innervations between these glutamatergic and GABAergic neurons are upregulated. Therefore, the co-activations of sensory cortices by pairing the input signals recruit their glutamatergic and GABAergic neurons to be associative memory cells, which undergo coordinated refinement among glutamatergic and GABAergic neurons as well as homeostatic plasticity among subcellular compartments in order to drive these cells toward the optimal state for the integrative storage of associated signals.

Prefrontal Cortical Neurons are Recruited as Secondary Associative Memory Cells for Associative Memory and Cognition

Prefrontal Cortical Neurons are Recruited as Secondary Associative Memory Cells for Associative Memory and Cognition

Associative memory cells and their working principle in the brain.

The acquisition, integration and storage of exogenous associated signals are termed as associative learning and memory. The consequences and processes of associative thinking and logical reasoning based on these stored exogenous signals can be memorized as endogenous signals, which are essential for decision making, intention, and planning. Associative memory cells recruited in these primary and secondary associative memories are presumably the foundation for the brain to fulfill cognition events and emotional reactions in life, though the plasticity of synaptic connectivity and neuronal activity has been believed to be involved in learning and memory. Current reports indicate that associative memory cells are recruited by their mutual synapse innervations among co-activated brain regions to fulfill the integration, storage and retrieval of associated signals. The activation of these associative memory cells initiates information recall in the mind, and the successful activation of their downstream neurons endorses memory presentations through behaviors and emotion reactions. In this review, we aim to draw a comprehensive diagram for associative memory cells, working principle and modulation, as well as propose their roles in cognition, emotion and behaviors.

Barrel Cortical Neuron Integrates Triple Associated Signals for Their Memory Through Receiving Epigenetic-Mediated New Synapse Innervations.

Associative learning is common way for information acquisition. Associative memory is essential to logical reasoning and associative thinking. The storages of multiple associated signals in individual neurons facilitate their integration, expand memory volume, and strengthen cognition ability. Associative memory cells that encode multiple signals have been reported, however, the mechanisms underlying their recruitment and working principle remain to be addressed. We have examined the recruitment of associative memory cells that integrate and store triple sensory signals as well as the potential mechanism of their recruitment. Paired mouse whisker, olfaction, and tail stimulations lead to odorant-induced motion and tail-induced whisker motion. In mice of expressing this cross-modal response, their barrel cortical neurons become to encode odor and tail signals alongside whisker signal. These barrel cortical neurons receive new synapse innervations from piriform and S1-tail cortical neurons. The emergence of cross-modal responses as well as the recruitments of new synapse innervations and associative memory cells in the barrel cortex need miRNA-324 and miRNA-133a, which downregulate Ttbk1 and Tet3. The co-activations of sensory cortices recruit their mutual synapse innervations and associative memory cells that integrate and store multiple associated signals through epigenetic-mediated process.

Synapse Innervation and Associative Memory Cell Are Recruited for Integrative Storage of Whisker and Odor Signals in the Barrel Cortex through miRNA-Mediated Processes.

Associative learning is a common way for information acquisition, and the integrative storage of multiple associated signals is essential for associative thinking and logical reasoning. In terms of the cellular mechanism for associative memory, our studies by behavioral task and cellular imaging demonstrate that paired whisker and odor stimulations lead to odorant-induced whisker motion and associative memory cell recruitment in the barrel cortex (BC), which is driven presumably by synapse innervation from co-activated sensory cortices. To confirm these associative memory cells and synapse innervations essential for associative memory and to examine their potential mechanisms, we studied a causal relationship between epigenetic process and memory cell/synapse recruitment by manipulating miRNAs and observing the changes from the recruitments of associative memory cells and synapse innervations to associative memory. Anti-miRNA-324 and anti-miRNA-133a in the BC significantly downregulate new synapse innervation, associative memory cell recruitment and odorant-induced whisker motion, where Tau-tubulin kinase-1 expression is increased. Therefore, the upregulated miRNA-324 in associative learning knocks down Ttbk1-mediated Tau phosphorylation and microtubule depolymerization, which drives the balance between polymerization and depolymerization toward the axon prolongation and spine stabilization to initiate new synapse innervations and to recruit associative memory cells.