Memory Circuitry Research Articles

Fear erasure in mice requires synergy between antidepressant drugs and extinction training.

Antidepressant drugs and psychotherapy combined are more effective in treating mood disorders than either treatment alone, but the neurobiological basis of this interaction is unknown. To investigate how antidepressants influence the response of mood-related systems to behavioral experience, we used a fear-conditioning and extinction paradigm in mice. Combining extinction training with chronic fluoxetine, but neither treatment alone, induced an enduring loss of conditioned fear memory in adult animals. Fluoxetine treatment increased synaptic plasticity, converted the fear memory circuitry to a more immature state, and acted through local brain-derived neurotrophic factor. Fluoxetine-induced plasticity may allow fear erasure by extinction-guided remodeling of the memory circuitry. Thus, the pharmacological effects of antidepressants need to be combined with psychological rehabilitation to reorganize networks rendered more plastic by the drug treatment.

Concussive Brain Injury Enhances Fear Learning and Excitatory Processes in the Amygdala

Mild traumatic brain injury (cerebral concussion) results in cognitive and emotional dysfunction. These injuries are a significant risk factor for the development of anxiety disorders, including posttraumatic stress disorder. However, because physically traumatic events typically occur in a highly emotional context, it is unknown whether traumatic brain injury itself is a cause of augmented fear and anxiety. Rats were trained with one of five fear-conditioning procedures (n = 105) 2 days after concussive brain trauma. Fear learning was assessed over subsequent days and chronic changes in fear learning and memory circuitry were assessed by measuring N-methyl-D-aspartate receptor subunits and glutamic acid decarboxylase, 67 kDa isoform protein levels in the hippocampus and basolateral amygdala complex (BLA). Injured rats exhibited an overall increase in fear conditioning, regardless of whether fear was retrieved via discrete or contextual-spatial stimuli. Moreover, injured rats appeared to overgeneralize learned fear to both conditioned and novel stimuli. Although no gross histopathology was evident, injury resulted in a significant upregulation of excitatory N-methyl-D-aspartate receptors in the BLA. There was a trend toward decreased γ-aminobutyric acid-related inhibition (glutamic acid decarboxylase, 67 kDa isoform) in the BLA and hippocampus. These results suggest that mild traumatic brain injury predisposes the brain toward heightened fear learning during stressful postinjury events and provides a potential molecular mechanism by which this occurs. Furthermore, these data represent a novel rodent model that can help advance the neurobiological and therapeutic understanding of the comorbidity of posttraumatic stress disorder and traumatic brain injury.

Adult-onset hypothyroidism enhances fear memory and upregulates mineralocorticoid and glucocorticoid receptors in the amygdala.

Hypothyroidism is the most common hormonal disease in adults, which is frequently accompanied by learning and memory impairments and emotional disorders. However, the deleterious effects of thyroid hormones deficiency on emotional memory are poorly understood and often underestimated. To evaluate the consequences of hypothyroidism on emotional learning and memory, we have performed a classical Pavlovian fear conditioning paradigm in euthyroid and adult-thyroidectomized Wistar rats. In this experimental model, learning acquisition was not impaired, fear memory was enhanced, memory extinction was delayed and spontaneous recovery of fear memory was exacerbated in hypothyroid rats. The potentiation of emotional memory under hypothyroidism was associated with an increase of corticosterone release after fear conditioning and with higher expression of glucocorticoid and mineralocorticoid receptors in the lateral and basolateral nuclei of the amygdala, nuclei that are critically involved in the circuitry of fear memory. Our results demonstrate for the first time that adult-onset hypothyroidism potentiates fear memory and also increases vulnerability to develop emotional memories. Furthermore, our findings suggest that enhanced corticosterone signaling in the amygdala is involved in the pathophysiological mechanisms of fear memory potentiation. Therefore, we recommend evaluating whether inappropriate regulation of fear in patients with post-traumatic stress and other mental disorders is associated with abnormal levels of thyroid hormones, especially those patients refractory to treatment.

Covariance modeling of MRI brain volumes in memory circuitry in schizophrenia: Sex differences are critical

Women have consistently demonstrated better verbal memory on tests that evaluate immediate and delayed free recall. In patients with schizophrenia, these verbal memory processes are relatively more preserved in women than men. However an understanding of the brain anatomy of the female advantage for verbal memory is still unclear.29 females and 59 males with schizophrenia made comparable to 21 female and 27 male healthy volunteers were scanned using structural magnetic resonance imaging (sMRI) in order to assess volumes of regions across the entire brain. Sex differences within and between groups in the covariance structure of memory circuitry regions were evaluated using a novel approach to covariance analysis (the Box M Test). Brain areas of interest included the prefrontal cortex (PFC), inferior parietal lobule (iPAR), anterior cingulate gyrus (ACG), parahippocampus, and hippocampus (HIPP).Results showed significant differences in the covariance matrices of females and males with schizophrenia compared with their healthy counterparts, in particular the relationships between iPAR–PFC, iPAR–ACG, and HIPP–PFC. Sex differences in the iPAR–PFC relationship were significantly associated with sex differences in verbal memory performance. In control women, but not in men ACG volume correlated strongly with memory performance. In schizophrenia, ACG volume was reduced in females, but not in men, relative to controls.Findings suggest that the relationship between iPAR and PFC is particularly important for understanding the relative preservation of verbal memory processing in females with schizophrenia and may compensate for ACG volume reductions. These results illustrate the utility of a unique covariance structure modeling approach that yields important new knowledge for understanding the nature of schizophrenia.

Subcortical Volumes in Long‐Term Abstinent Alcoholics: Associations With Psychiatric Comorbidity

Research in chronic alcoholics on memory, decision-making, learning, stress, and reward circuitry has increasingly highlighted the importance of subcortical brain structures. In addition, epidemiological studies have established the pervasiveness of co-occurring psychiatric diagnoses in alcoholism. Subcortical structures have been implicated in externalizing pathology, including alcohol dependence, and in dysregulated stress and reward circuitry in anxiety and mood disorders and alcohol dependence. Most studies have focused on active or recently detoxified alcoholics, while subcortical structures in long-term abstinent alcoholics (LTAA) have remained relatively uninvestigated. Structural MRI was used to compare volumes of 8 subcortical structures (lateral ventricles, thalamus, caudate, putamen, pallidum, hippocampus, amygdala, and nucleus accumbens) in 24 female and 28 male LTAA (mean abstinence=6.3 years, mean age= 46.6 years) and 23 female and 25 male nonalcoholic controls (NAC) (mean age=45.6 years) to explore relations between subcortical brain volumes and alcohol use measures in LTAA and relations between subcortical volumes and psychiatric diagnoses and symptom counts in LTAA and NAC. We found minimal differences between LTAA and NAC in subcortical volumes. However, in LTAA, but not NAC, volumes of targeted subcortical structures were smaller in individuals with versus without comorbid lifetime or current psychiatric diagnoses, independent of lifetime alcohol consumption. Our finding of minimal differences in subcortical volumes between LTAA and NAC is consistent with LTAA never having had volume deficits in these regions. However, given that imaging studies have frequently reported smaller subcortical volumes in active and recently detoxified alcoholics compared to controls, our results are also consistent with the recovery of subcortical volumes with sustained abstinence. The finding of persistent smaller subcortical volumes in LTAA, but not NAC, with comorbid psychiatric diagnoses, suggests that the smaller volumes are a result of the combined effects of chronic alcohol dependence and psychiatric morbidity and suggests that a comorbid psychiatric disorder (even if not current) interferes with the recovery of subcortical volumes.

Endogenous Expression of Matriptase in Neural Progenitor Cells Promotes Cell Migration and Neuron Differentiation

Recent studies show that type II transmembrane serine proteases play important roles in diverse cellular activities and pathological processes. Their expression and functions in the central nervous system, however, are largely unexplored. In this study, we show that the expression of one such member, matriptase (MTP), was cell type-restricted and primarily expressed in neural progenitor (NP) cells and neurons. Blocking MTP expression or MTP activity prevented NP cell traverse of reconstituted basement membrane, whereas overexpression of MTP promoted it. The NP cell mobilization induced by either vascular endothelial growth factor or hepatocyte growth factor was also impaired by knocking down MTP expression. MTP acts upstream of matrix metalloproteinase 2 in promoting NP cell mobility. In embryonic stem cell differentiation to neural cells, MTP knockdown had no effect on entry of embryonic stem cells into the neural lineage. High MTP expression or activity, however, shifts the population dynamics from NP cells toward neurons to favor neuronal differentiation. This is the first report to demonstrate the direct involvement of type II transmembrane serine protease in NP cell function.

Emotion Processing Influences Working Memory Circuits in Pediatric Bipolar Disorder and Attention-Deficit/Hyperactivity Disorder

This functional magnetic resonance imaging (fMRI) study examined how working memory circuits are affected by face emotion processing in pediatric bipolar disorder (PBD) and attention-deficit/hyperactivity disorder (ADHD). A total of 23 patients with PBD, 14 patients with ADHD, and 19 healthy control (HC) subjects (mean age, 13.36 ± 2.55 years) underwent an affective, two-back fMRI task with blocks of happy, angry, and neutral faces. For angry versus neutral faces PBD patients, relative to ADHD patients, exhibited increased activation in the subgenual anterior cingulate cortex (ACC) and orbitofrontal cortex, and reduced activation in the dorsolateral prefrontal cortex (DLPFC) and premotor cortex. Relative to the HC group, the PBD group showed no increased activation and reduced activation at the junction of DLPFC and ventrolateral prefrontal cortex (VLPFC). Relative to HC, the ADHD patients exhibited greater activation in the DLPFC and reduced activation in the ventral and medial PFC, pregenual ACC, striatum, and temporo-parietal regions. For happy versus neutral faces, relative to the ADHD group, the PBD group exhibited greater activation in the bilateral caudate, and relative to the HC group the ADHD group showed increased activation in the DLPFC, striatal, and parietal regions, and no reduced activation. The ADHD group, compared with the HC group, showed no reduced activation and increased activation in regions that were underactive for the angry face condition. Relative to the ADHD group, the PBD group exhibited greater deployment of the emotion-processing circuitry and reduced deployment of working memory circuitry. Commonalities across PBD and ADHD patients, relative to the HC individuals, entailed cortico-subcortical activity that was reduced under negative emotional challenge and increased under positive emotional challenge.

MRI correlates of episodic memory in Alzheimer's disease, mild cognitive impairment, and healthy aging

Episodic memory is a core feature of Alzheimer's disease (AD) and mild cognitive impairment (MCI). Impaired episodic memory in AD results from the dysfunction of an integrated network and involves both gray and white matter pathologies. We explored the neural correlates of episodic memory in AD, MCI and healthy aging by correlating a measure of episodic memory with hippocampal volume and fractional anisotropy (FA) and mean diffusivity (MD) of the cingulum and fornix. Episodic memory was associated with hippocampal volume and MD of the cingulum and fornix. In contrast, there were fewer significant associations between episodic memory and FA. These findings support a relationship between episodic memory and hippocampal circuitry, and suggest that MD is a more sensitive marker of decreased white matter integrity in the study of AD and MCI than FA. Furthermore, MD was significantly associated with hippocampal volume, indicating that white matter pathology is not completely independent of gray matter pathology. However, the pattern of diffusivity differences in AD and MCI implies a more complex pathology than simply Wallerian degeneration.

Anterior thalamus deep brain stimulation at high current impairs memory in rats

Deep brain stimulation (DBS) of the anterior thalamic nucleus (AN), an important relay in the circuitry of memory, is currently being proposed as a treatment for epilepsy. Despite the encouraging results with the use of this therapy, potential benefits and adverse effects are yet to be determined. We show that AN stimulation at relatively high current disrupted the acquisition of contextual fear conditioning and impaired performance on a spatial alternating task in rats. This has not been observed at parameters generating a charge density that approximated the one used in clinical practice. At settings that impaired behavior, AN stimulation induced a functional depolarization block nearby the electrode, increased c-Fos expression in cerebral regions projecting to and receiving projections from the AN, and influenced hippocampal activity. This suggests that complex mechanisms might be involved in the effects of AN DBS, including a local target inactivation and the modulation of structures at a distance. Though translating data from animals to humans has to be considered with caution, our study underscores the need for carefully monitoring memory function while selecting stimulation parameters during the clinical evaluation of AN DBS.

Perisynaptic GluR2-lacking AMPA receptors control the reversibility of synaptic and spines modifications

How persistent synaptic and spine modification is achieved is essential to our understanding of developmental refinement of neural circuitry and formation of memory. Within a short period after their induction, both types of modifications can either be stabilized or reversed, but how this reversibility is controlled is largely unknown. We have shown previously that AMPA receptors (AMPARs) are delivered to perisynaptic regions after the induction of long-term potentiation (LTP) but are absent from perisynaptic regions after the full expression of LTP. Here, we report that perisynaptic AMPARs are GluR2-lacking and they translocate to synapses in a protein kinase C (PKC)-dependent manner. Once entering synapses, these AMPARs quickly switch to GluR2-containing in an activity-dependent manner. Absence of postinduction activity or blocking interactions between GluR2 and NSF, or GluR2 and GRIP/PICK1 results in LTP mediated by GluR2-lacking AMPARs. However, these synaptic GluR2-lacking AMPARs are not sufficient to allow reversibility of LTP. On the other hand, postsynaptic inhibition of PKC activity holds AMPARs at perisynaptic regions. As long as perisynaptic AMPARs are present, both LTP and spine expansion remain labile: they can be reverted to the baseline state together with removal of perisynaptic AMPARs, or they can enter a stabilized state of persistent increase together with synaptic incorporation of perisynaptic AMPARs. Thus, perisynaptic GluR2-lacking AMPARs play a critical role in controlling the reversibility of both synaptic and spine modifications.

Working memory circuitry in schizophrenia shows widespread cortical inefficiency and compensation

Background Working memory studies in schizophrenia (SZ), using functional magnetic resonance imaging (fMRI) and univariate analyses, have led to observations of hypo- or hyperactivation of discrete cortical regions and subsequent interpretations (e.g. neural inefficiencies). We employed a data-driven, multivariate analysis to identify the patterns of brain–behavior relationships in SZ during working memory. Methods fMRI scans were collected from 13 SZ and 18 healthy control (HC) participants performing a modified Sternberg item recognition paradigm with three memory loads. We applied partial least squares analysis (PLS) to assess brain activation during the task both alone and with behavioral measures (accuracy and response time, RT) as covariates. Results While the HC primary pattern was not affected by increasing load demands, SZ participants showed an exaggerated change in the Blood Oxygenation Level Dependent (BOLD) signal from the low to moderate memory load conditions and subsequent decrease in the greatest memory load, in frontal, motor, parietal and subcortical areas. With behavioral covariates, the separate groups identified distinct brain–behavior relationships and circuits. Increased activation of the middle temporal gyrus was associated with greater accuracy and faster RT only in SZ. Conclusions The inverted U-shaped curves in the SZ BOLD signal in the same areas that show flat activation in the HC data indicate widespread neural inefficiency in working memory in SZ. While both groups performed the task with similar levels of accuracy, participants with schizophrenia show a compensatory network of different sub-regions of the prefrontal cortex, parietal lobule, and the temporal gyri in this working memory task.

A Neural Circuit Mechanism Integrating Motivational State with Memory Expression in Drosophila

Behavioral expression of food-associated memory in fruit flies is constrained by satiety and promoted by hunger, suggesting an influence of motivational state. Here, we identify a neural mechanism that integrates the internal state of hunger and appetitive memory. We show that stimulation of neurons that express neuropeptide F (dNPF), an ortholog of mammalian NPY, mimics food deprivation and promotes memory performance in satiated flies. Robust appetitive memory performance requires the dNPF receptor in six dopaminergic neurons that innervate a distinct region of the mushroom bodies. Blocking these dopaminergic neurons releases memory performance in satiated flies, whereas stimulation suppresses memory performance in hungry flies. Therefore, dNPF and dopamine provide a motivational switch in the mushroom body that controls the output of appetitive memory.

A systematic fMRI investigation of the brain systems subserving different working memory components in schizophrenia

Working memory impairment is one of the cardinal cognitive disturbances in schizophrenia and considerable evidence suggests that it can be traced to functional alterations in the brain. The exact allocation of specific deficits to regional specific dysfunctions, however, remains elusive. The aim of this study was to examine the functional integrity of three distinguishable brain systems underlying maintenance-related subprocesses of working memory (articulatory rehearsal, non-articulatory maintenance of phonological information, maintenance of visuospatial information) in patients with schizophrenia. Using an experimental paradigm, which had been designed to selectively activate these different brain systems, we assessed the brain activation of patients and controls with functional magnetic resonance imaging. Compared with controls, patients showed reduced activation of the fronto-opercular, intraparietal and anterior cingulate cortex during the non-articulatory maintenance of phonological information, as well as attenuated deactivation of the hippocampus. Additionally, we found prefrontal activation to depend critically on the patients' current symptom status. During visuospatial maintenance, patients showed impaired activation of the superior parietal, temporal and occipital cortex, combined with enhanced activation of the frontal eye field and the inferior parietal cortex. No abnormal activations were observed during the articulatory rehearsal task. All activation differences were independent of group differences in task performance. Our fine-grained analysis of dysfunctions in particular aspects of working memory circuitry provides evidence for a differential impairment of the brain systems supporting working memory subcomponents in schizophrenia and extends knowledge of the relationship between cognitive deficits, brain activation abnormalities and symptoms in schizophrenia.

Prechemotherapy alterations in brain function in women with breast cancer

Despite clinical reports of cognitive deficits associated with cancer chemotherapy, the underlying brain mechanisms are not clear. This research examined selective attention and working memory using functional magnetic resonance imaging (fMRI) in women before chemotherapy for localized breast cancer. Patients were tested with an established selective attention and working memory task during fMRI. Compared with healthy controls, patients showed (a) bilateral brain activation in high-demand task conditions with recruitment of additional components of attention/working memory circuitry, and (b) less accurate and slower task performance. Results indicate compromised cognitive functioning before any chemotherapy and raise key questions for further research.

Probing Verbal Working Memory Circuitry by the Analysis of BOLD Contrast Response Functions and Structural Equation Models

Probing Verbal Working Memory Circuitry by the Analysis of BOLD Contrast Response Functions and Structural Equation Models

Adult learning and remodeling of hippocampal mossy fibers: Unheralded participant in circuitry for long‐lasting spatial memory

Two articles in this issue concerning the overexpression of GAP-43 on mossy fiber growth are related to the plasticity of these axons in relation to learning and memory.

Mind-Body Intervention can Reduce Seizures and Improve Quality of Life for Epilepsy Patients

In the coming years the number of patients with cognitive disorders, such as Alzheimer disease and traumatic brain injury, is expected to dramatically increase, leading to an ever-increasing societal cost. Unfortunately, few medical and pharmacologic treatments have shown tangible benefit in the treatment of these diseases. Deep brain stimulation (DBS) is an established surgical technique to address multiple conditions, including Parkinson disease and essential tremor. Data from patients being treated with DBS, as well as those being monitored for seizures with depth electrodes, have suggested improvement in memory with electrical neuromodulation.MEDLINE was searched from inception through March 2018 using the keywords “DBS,” “Deep Brain Stimulation,” “Memory,” “Memory Modulation,” and “Cognition.” Studies evaluating the effect of DBS on memory and learning were shortlisted and reviewed.Efforts to stimulate various nodes within the memory circuitry suggest that the variable effects may result from different mechanisms, including alteration of neural firing patterns, increased activity across several regions, and amplification of neural plasticity. Some of these targets, such as the entorhinal cortex, hippocampus, and nucleus basalis of Meynert, have shown promising results with regards to modulation of memory.Given the aging population and increasing numbers of patients with memory impairment from neurodegenerative diseases, interest in neuromodulation for memory enhancement will likely expand. Further work should employ more sophisticated responsive stimulation parameters and precise spatial targeting that may lead to an effective stimulation strategy for memory enhancement.

The Octopus Vertical Lobe Modulates Short-Term Learning Rate and Uses LTP to Acquire Long-Term Memory

Analyzing the processes and neuronal circuitry involved in complex behaviors in phylogenetically remote species can help us understand the evolution and function of these systems. Cephalopods, with their vertebrate-like behaviors but much simpler brains, are ideal for such an analysis. The vertical lobe (VL) of Octopus vulgaris is a pivotal brain station in its learning and memory system. To examine the organization of the learning and memory circuitry and to test whether the LTP that we discovered in the VL is involved in behavioral learning, we tetanized the VL to induce a global synaptic enhancement of the VL pathway. The effects of tetanization on learning and memory of a passive avoidance task were compared to those of transecting the same pathway. Tetanization accelerated and transection slowed short-term learning to avoid attacking a negatively reinforced object. However, both treatments impaired long-term recall the next day. Our results suggest that the learning and memory system in the octopus, as in mammals [9], is separated into short- and long-term memory sites. In the octopus, the two memory sites are not independent; the VL, which mediates long-term memory acquisition through LTP, also modulates the circuitry controlling behavior and short-term learning.

Mitigating Soft Errors in SRAM Address Decoders Using Built-in Current Sensors

In this paper, we propose a diagnose strategy based on built-in current sensors able to detect the effects of single event transients (SETs) in SRAM memory decoders. By analyzing the effects, it is possible to mitigate the error by warning the system about the erroneous write and read operation or by circuit error correction avoiding catastrophic multiple bit upset errors. While EDAC can only protect faults in the memory cell array, the proposed method can cope with faults in the combinational memory circuitry. This BICS-based technique can be used in combination with EDAC to achieve high reliability in memories fabricated in nanometer technologies. Our methodology has been validated by Spice simulation and results show that our approach presents a low area, performance and power dissipation penalty.

Mind the Brain

First two paragraph... The mind-body problem has lain at the heart of the way we think about human nature throughout modern thought. It became a problem for science in the early nineteenth century when efforts were first made to provide systematic observations on the relationship between mind and brain. Today we are witnessing a revolution in neuroscience, as researchers chart the circuitry of memory, cognition, and emotion, offering the promise of a chemically based medicine of the mind. But these same words would have been use as apt over 300 years ago, when neurology first emerged as an experimental science.