Scalable Phylogeny Reconstruction with Disaggregated Near-memory Processing

Disaggregated computer architectures eliminate resource fragmentation in next-generation datacenters by enabling virtual machines to employ resources such as CPUs, memory, and accelerators that are physically located on different servers. While this paves the way for highly compute- and/or memory-intensive applications to potentially deploy all CPUs and/or memory resources in a datacenter, it poses a major challenge to the efficient deployment of hardware accelerators: input/output data can reside on different servers than the ones hosting accelerator resources, thereby requiring time- and energy-consuming remote data transfers that diminish the gains of hardware acceleration. Targeting a disaggregated datacenter architecture similar to the IBM dReDBox disaggregated datacenter prototype, the present work explores the potential of deploying custom acceleration units adjacently to the disaggregated-memory controller on memory bricks (in dReDBox terminology), which is implemented on FPGA technology, to reduce data movement and improve performance and energy efficiency when reconstructing large phylogenies (evolutionary relationships among organisms). A fundamental computational kernel is the Phylogenetic Likelihood Function (PLF), which dominates the total execution time (up to 95%) of widely used maximum-likelihood methods. Numerous efforts to boost PLF performance over the years focused on accelerating computation; since the PLF is a data-intensive, memory-bound operation, performance remains limited by data movement, and memory disaggregation only exacerbates the problem. We describe two near-memory processing models, one that addresses the problem of workload distribution to memory bricks, which is particularly tailored toward larger genomes (e.g., plants and mammals), and one that reduces overall memory requirements through memory-side data interpolation transparently to the application, thereby allowing the phylogeny size to scale to a larger number of organisms without requiring additional memory.

Lateral entorhinal cortex inputs modulate hippocampal dendritic excitability by recruiting a local disinhibitory microcircuit

The lateral entorhinal cortex (LEC) provides information about multi-sensory environmental cues to the hippocampus through direct inputs to the distal dendrites of CA1 pyramidal neurons. A growing body of work suggests that LEC neurons perform important functions for episodic memory processing, coding for contextually-salient elements of an environment or the experience within it. However, we know little about the functional circuit interactions between LEC and the hippocampus. In this study, we combine functional circuit mapping and computational modeling to examine how long-range glutamatergic LEC projections modulate compartment-specific excitation-inhibition dynamics in hippocampal area CA1. We demonstrate that glutamatergic LEC inputs can drive local dendritic spikes in CA1 pyramidal neurons, aided by the recruitment of a disinhibitory vasoactive intestinal peptide (VIP)-expressing inhibitory neuron microcircuit. Our circuit mapping further reveals that, in parallel, LEC also recruits cholecystokinin (CCK)-expressing inhibitory neurons, which our model predicts act as a strong suppressor of dendritic spikes. These results provide new insight into a cortically-driven GABAergic microcircuit mechanism that gates non-linear dendritic computations, which may support compartment-specific coding of multi-sensory contextual features within the hippocampus.

Prelimbic proBDNF facilitates memory destabilization by regulation of neuronal function in juveniles

Fear regulation changes as a function of age and adolescence is a key developmental period for the continued maturation of fear neural circuitry. The involvement of prelimbic proBDNF in fear memory extinction and its mediated signaling were reported previously. Given the inherent high level of proBDNF during juvenile period, we tested whether prelimbic proBDNF regulated synaptic and neuronal functions allowing to influencing retrieval-dependent memory processing. By examining freezing behavior of auditory fear conditioned rats, we found high levels of prelimbic proBDNF in juvenile rats enhanced destabilization of the retrieval-dependent weak but not strong fear memory through activating p75NTR-GluN2B signaling. This modification was attributed to the increment in proportion of thin type spine and promotion in synaptic function, as evidence by facilitation of NMDA-mediated EPSCs and GluN2B-dependent synaptic depression. The strong prelimbic theta- and gamma-oscillation coupling predicted the suppressive effect of proBDNF on the recall of post-retrieval memory. Our results critically emphasize the importance of developmental proBDNF for modification of retrieval-dependent memory and provide a potential critical targeting to inhibit threaten memories associated with neurodevelopment disorders.

Choline Transporter regulates olfactory habituation via a neuronal triad of excitatory, inhibitory and mushroom body neurons

Choline is an essential component of Acetylcholine (ACh) biosynthesis pathway which requires high-affinity Choline transporter (ChT) for its uptake into the presynaptic terminals of cholinergic neurons. Previously, we had reported a predominant expression of ChT in memory processing and storing region of the Drosophila brain called mushroom bodies (MBs). It is unknown how ChT contributes to the functional principles of MB operation. Here, we demonstrate the role of ChT in Habituation, a non-associative form of learning. Odour driven habituation traces are laid down in ChT dependent manner in antennal lobes (AL), projection neurons (PNs), and MBs. We observed that reduced habituation due to knock-down of ChT in MBs causes hypersensitivity towards odour, suggesting that ChT also regulates incoming stimulus suppression. Importantly, we show for the first time that ChT is not unique to cholinergic neurons but is also required in inhibitory GABAergic neurons to drive habituation behaviour. Our results support a model in which ChT regulates both habituation and incoming stimuli through multiple circuit loci via an interplay between excitatory and inhibitory neurons. Strikingly, the lack of ChT in MBs shows characteristics similar to the major reported features of Autism spectrum disorders (ASD), including attenuated habituation, sensory hypersensitivity as well as defective GABAergic signalling. Our data establish the role of ChT in habituation and suggest that its dysfunction may contribute to neuropsychiatric disorders like ASD.

Reactivation-dependent amnesia for object recognition memory is contingent on hippocampal theta–gamma coupling during recall

Hippocampal dopamine D1/D5 receptor-dependent destabilization is necessary for object recognition memory (ORM) updating through reconsolidation. Dopamine also regulates hippocampal theta and gamma oscillations, which are involved in novelty and memory processing. We found that, in adult male rats, ORM recall in the presence of a novel object, but not in the presence of a familiar one, triggers hippocampal theta–gamma coupling. Hippocampal theta–gamma coupling (hPAC) does not happen when ORM destabilization is prevented by blocking D1/D5 receptors, but artificial hPAC generation during recall in the presence of a familiar object enables the amnesic effect of reconsolidation inhibitors. Therefore, hPAC controls ORM destabilization, and its modulation could increase reconsolidation-based psychotherapy efficacy.

Competitive dynamics underlie cognitive improvements during sleep

We provide evidence that human sleep is a competitive arena in which cognitive domains vie for limited resources. Using pharmacology and effective connectivity analysis, we demonstrate that long-term memory and working memory are served by distinct offline neural mechanisms that are mutually antagonistic. Specifically, we administered zolpidem to increase central sigma activity and demonstrated targeted suppression of autonomic vagal activity. With effective connectivity, we determined the central activity has greater causal influence over autonomic activity, and the magnitude of this influence during sleep produced a behavioral trade-off between offline long-term and working memory processing. These findings suggest a sleep switch mechanism that toggles between central sigma-dependent long-term memory and autonomic vagal-dependent working memory processing.

Glutamate as a Stressoric Factor for the Ex Vivo Release of Catecholamines from the Rabbit Medial Prefrontal Cortex (mPFC)

One of the major roles of glutamic acid (Glu) is to serve as an excitatory neurotransmitter within the central nervous system (CNS). This amino acid influences the activity of several brain areas, including the thalamus, brainstem, spinal cord, basal ganglia, and pons. Catecholamines (CAs) are synthesized in the brain and adrenal medulla and by some sympathetic nerve fibers. CAs, including dopamine (DA), norepinephrine (NE), and epinephrine (E), are the principal neurotransmitters that mediate a variety of CNS functions, such as motor control, cognition, emotion, memory processing, pain, stress, and endocrine modulation. This study aims to investigate the effects of the application of various Glu concentrates (5, 50, and 200 µM) on CAs release from rabbit medial prefrontal cortex (mPFC) slices and compare any resulting correlations with CAs released from the hypothalamus during 90 min of incubation. Medial prefrontal cortex samples were dissected from decapitated, twelve-week-old female rabbits. The results demonstrated that Glu differentially influences the direct release of CAs from the mPFC and the indirect release of CAs from the hypothalamus. When under stress, the hypothalamus, a central brain structure of the HPA axis, induces and adapts such processes. Generally, there was an inhibitory effect of Glu on CAs release from mPFC slices. Our findings show that the effect arises from Glu’s action on higher-order motivational structures, which may indicate its contribution to the stress response by modulating the amount of CAs released.

Effects of Tinnitus on Cognition and Depressive Symptoms Over Time

Evidence suggests links among tinnitus, depression, and cognition. We examined these associations over time. We hypothesized baseline tinnitus would predict poorer cognitive performance and more depressive symptoms an average of 11.4 years later. We examined 839 men at two timepoints (baseline age M=55.94; follow-up age M=67.56). At each time point participants responded yes/no if they had tinnitus. We created three tinnitus status groups – no tinnitus at either time, tinnitus at both, and no tinnitus at baseline but tinnitus at follow-up. At both time points we measured cognitive performance with tests of episodic memory, processing speed, executive function, and verbal fluency. Depressive symptoms were based on the Center for Epidemiological Studies Depression scale. There was no association between tinnitus and any measure of cognitive performance. Depressive symptoms declined from baseline to follow-up. In separate mixed models predicting depressive symptoms, there was a significant main effect for tinnitus status at baseline (p = .003) and follow-up (p < .001). Those with tinnitus at both times had significantly higher depressive symptoms than the “No tinnitus” group (p < .001). This association remained significant after accounting for baseline depressive symptoms (p = .011) at follow-up. Results did not support the hypothesis that tinnitus would be associated with poorer cognitive function. However, depressive symptoms declined among those with no tinnitus than the other groups. The relationship between tinnitus and depressive symptoms may have implications for future cognitive performance among older adults, given previous evidence that depressive symptoms are risk factors for cognitive decline.

Subjective and Perseverative Cognition Mediate the Relationship Between Sleep and Work Impairment

The study examined the mediating role of subjective and perseverative cognition on sleep and work impairment. Sixty nurses completed a background survey and 14-days of ecological momentary assessments (EMA) and sleep actigraphy. Each day, participants evaluated their subjective cognition (mental sharpness, memory, processing speed), perseverative cognition (rumination) and work impairment (how much did you cut back on normal paid work, how much did the quality of your work suffer). Multiple sleep characteristics were measured by EMA and actigraphy. Multilevel mediation models adjusted for sociodemographics and work shift. At the between-person and within-person levels, there were mediated associations of sleep quality and sufficiency (but not actigraphy-measured sleep) with work impairment through subjective and perseverative cognition. Better sleep quality or higher sleep sufficiency were associated with better subjective and perseverative cognition, which, in turn, were associated with less work impairment.