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Translational Psychiatry Feb 2024Memory persistence is a double edge sword. Persistence of adaptive memories is essential for survival and even determines who we are. Neurodegenerative conditions with... (Review)
Review
Memory persistence is a double edge sword. Persistence of adaptive memories is essential for survival and even determines who we are. Neurodegenerative conditions with significant memory loss such as Alzheimer's disease, testify how defects of memory persistence have severe and irreversible effects on personality, among other symptoms. Yet, maintenance of overly strong maladaptive memories underlies highly debilitating psychiatric conditions including post-traumatic stress disorder, specific phobia, substance dependence and binge eating disorder. Here we review the neurobiological mechanisms supporting memory formation, persistence, inhibition and forgetting. We then shift the focus to how such mechanisms have been exploited to alter the persistence of laboratory-generated memories in human healthy volunteers as a proof of concept. Finally, we review the effect of behavioural and pharmacological interventions in anxiety and addiction disorder patients, highlighting key findings, gaps, and future directions for basic and translational research.
Topics: Humans; Anxiety Disorders; Stress Disorders, Post-Traumatic; Phobic Disorders; Substance-Related Disorders; Memory Disorders
PubMed: 38355584
DOI: 10.1038/s41398-024-02808-z -
International Journal of Environmental... Aug 2023Schizophrenia (SCZ) and bipolar disorder (BD) are severe psychiatric disorders that share clinical features and several risk genes. Important information about their... (Review)
Review
Schizophrenia (SCZ) and bipolar disorder (BD) are severe psychiatric disorders that share clinical features and several risk genes. Important information about their genetic underpinnings arises from intermediate phenotypes (IPs), quantifiable biological traits that are more prevalent in unaffected relatives (RELs) of patients compared to the general population and co-segregate with the disorders. Within IPs, neuropsychological functions and neuroimaging measures have the potential to provide useful insight into the pathophysiology of SCZ and BD. In this context, the present narrative review provides a comprehensive overview of the available evidence on deficits in neuropsychological functions and neuroimaging alterations in unaffected relatives of SCZ (SCZ-RELs) and BD (BD-RELs). Overall, deficits in cognitive functions including intelligence, memory, attention, executive functions, and social cognition could be considered IPs for SCZ. Although the picture for cognitive alterations in BD-RELs is less defined, BD-RELs seem to present worse performances compared to controls in executive functioning, including adaptable thinking, planning, self-monitoring, self-control, and working memory. Among neuroimaging markers, SCZ-RELs appear to be characterized by structural and functional alterations in the cortico-striatal-thalamic network, while BD risk seems to be associated with abnormalities in the prefrontal, temporal, thalamic, and limbic regions. In conclusion, SCZ-RELs and BD-RELs present a pattern of cognitive and neuroimaging alterations that lie between patients and healthy individuals. Similar abnormalities in SCZ-RELs and BD-RELs may be the phenotypic expression of the shared genetic mechanisms underlying both disorders, while the specificities in neuropsychological and neuroimaging profiles may be associated with the differential symptom expression in the two disorders.
PubMed: 37569080
DOI: 10.3390/ijerph20156540 -
Nature Communications Sep 2023Social recognition memory (SRM) is a key determinant of social interactions. While the cerebellum emerges as an important region for social behavior, how cerebellar...
Social recognition memory (SRM) is a key determinant of social interactions. While the cerebellum emerges as an important region for social behavior, how cerebellar activity affects social functions remains unclear. We selectively increased the excitability of molecular layer interneurons (MLIs) to suppress Purkinje cell firing in the mouse cerebellar vermis. Chemogenetic perturbation of MLIs impaired SRM without affecting sociability, anxiety levels, motor coordination or object recognition. Optogenetic interference of MLIs during distinct phases of a social recognition test revealed the cerebellar engagement in the retrieval, but not encoding, of social information. c-Fos mapping after the social recognition test showed that cerebellar manipulation decreased brain-wide interregional correlations and altered network structure from medial prefrontal cortex and hippocampus-centered to amygdala-centered modules. Anatomical tracing demonstrated hierarchical projections from the central cerebellum to the social brain network integrating amygdalar connections. Our findings suggest that the cerebellum organizes the neural matrix necessary for SRM.
Topics: Mice; Animals; Cerebellar Vermis; Cerebellum; Purkinje Cells; Interneurons; Memory Disorders
PubMed: 37752149
DOI: 10.1038/s41467-023-41744-2 -
Translational Psychiatry Dec 2023Current evidence-based treatments for post-traumatic stress disorder (PTSD) are efficacious in only part of PTSD patients. Therefore, novel neurobiologically informed... (Meta-Analysis)
Meta-Analysis
Current evidence-based treatments for post-traumatic stress disorder (PTSD) are efficacious in only part of PTSD patients. Therefore, novel neurobiologically informed approaches are urgently needed. Clinical and translational neuroscience point to altered learning and memory processes as key in (models of) PTSD psychopathology. We extended this notion by clarifying at a meta-level (i) the role of information valence, i.e. neutral versus emotional/fearful, and (ii) comparability, as far as applicable, between clinical and preclinical phenotypes. We hypothesized that cross-species, neutral versus emotional/fearful information processing is, respectively, impaired and enhanced in PTSD. This preregistered meta-analysis involved a literature search on PTSD+Learning/Memory+Behavior, performed in PubMed. First, the effect of information valence was estimated with a random-effects meta-regression. The sources of variation were explored with a random forest-based analysis. The analyses included 92 clinical (N = 6732 humans) and 182 preclinical (N = 6834 animals) studies. A general impairment of learning, memory and extinction processes was observed in PTSD patients, regardless of information valence. Impaired neutral learning/memory and fear extinction were also present in animal models of PTSD. Yet, PTSD models enhanced fear/trauma memory in preclinical studies and PTSD impaired emotional memory in patients. Clinical data on fear/trauma memory was limited. Mnemonic phase and valence explained most variation in rodents but not humans. Impaired neutral learning/memory and fear extinction show stable cross-species PTSD phenotypes. These could be targeted for novel PTSD treatments, using information gained from neurobiological animal studies. We argue that apparent cross-species discrepancies in emotional/fearful memory deserve further in-depth study; until then, animal models targeting this phenotype should be applied with utmost care.
Topics: Animals; Humans; Stress Disorders, Post-Traumatic; Fear; Extinction, Psychological; Learning; Memory; Memory Disorders
PubMed: 38062029
DOI: 10.1038/s41398-023-02660-7 -
Brain, Behavior, and Immunity Oct 2023Concentrations of pro-inflammatory cytokines -interleukin-6 (IL-6) and interleukin-8 (IL-8) - are increased with age and in Alzheimer's disease (AD). It is not clear...
Concentrations of pro-inflammatory cytokines -interleukin-6 (IL-6) and interleukin-8 (IL-8) - are increased with age and in Alzheimer's disease (AD). It is not clear whether concentrations of IL-6 and IL-8 in the central nervous system predict later brain and cognitive changes over time nor whether this relationship is mediated by core AD biomarkers. Here, 219 cognitively healthy older adults (62-91 years), with baseline cerebrospinal fluid (CSF) measures of IL-6 and IL-8 were followed over time - up to 9 years - with assessments that included cognitive function, structural magnetic resonance imaging, and CSF measurements of phosphorylated tau (p-tau) and amyloid-β (Aβ-42) concentrations (for a subsample). Higher baseline CSF IL-8 was associated with better memory performance over time in the context of lower levels of CSF p-tau and p-tau/Aβ-42 ratio. Higher CSF IL-6 was related to less CSF p-tau changes over time. The results are in line with the hypothesis suggesting that an up-regulation of IL-6 and IL-8 in the brain may play a neuroprotective role in cognitively healthy older adults with lower load of AD pathology.
Topics: Humans; Aged; Alzheimer Disease; Interleukin-6; Interleukin-8; tau Proteins; Amyloid beta-Peptides; Brain; Biomarkers; Atrophy; Memory Disorders; Cognitive Dysfunction; Peptide Fragments
PubMed: 37400002
DOI: 10.1016/j.bbi.2023.06.027 -
Neurobiology of Disease Aug 2023Increasing evidence indicates that a key factor in neurodegenerative diseases is the activation of the unfolded protein response (UPR) caused by an accumulation of...
Increasing evidence indicates that a key factor in neurodegenerative diseases is the activation of the unfolded protein response (UPR) caused by an accumulation of misfolded proteins in the endoplasmic reticulum (ER stress). Particularly, in Huntington's disease (HD) mutant huntingtin (mHtt) toxicity involves disruption of the ER-associated degradation pathway and loss of the ER protein homeostasis leading to neuronal dysfunction and degeneration. Besides the role of the UPR in regulating cell survival and death, studies that demonstrate the contribution of sustained UPR activation, particularly of PERK signaling, in memory disturbances and synaptic plasticity deficiencies are emerging. Given the contribution of hippocampal dysfunction to emotional and cognitive deficits seen in HD, we have analyzed the involvement of ER stress in HD memory alterations. We have demonstrated that at early disease stages, ER stress activation manifested as an increase in GRP78 and CHOP is observed in the hippocampus of R6/1 mice. Genetic reduction of GRP78 expression resulted in preventing hippocampal-dependent memory alterations but no motor deficits. Accordingly, hippocampal neuropathology namely, dendritic spine loss and accumulation of mHtt aggregates was ameliorated by GRP78 reduction. To elucidate the signaling pathways, we found that the inactivation of PERK by GSK2606414 restored spatial and recognition memories in R6/1 mice and rescued dendritic spine density in CA1 pyramidal neurons and protein levels of some specific immediate early genes. Our study unveils the critical role of the GRP78/PERK axis in memory impairment in HD mice and suggests the modulation of PERK activation as a novel therapeutic target for HD intervention.
Topics: Animals; Mice; Cognition Disorders; Disease Models, Animal; Endoplasmic Reticulum Chaperone BiP; Huntingtin Protein; Huntington Disease; Memory Disorders; Mice, Transgenic
PubMed: 37442396
DOI: 10.1016/j.nbd.2023.106225 -
Noro Psikiyatri Arsivi 2023Newly acquired memory traces have been thought to become stable and resistant to interruption after they are stored in long-term memory. However, according to a recent... (Review)
Review
Newly acquired memory traces have been thought to become stable and resistant to interruption after they are stored in long-term memory. However, according to a recent research drugs such as beta-adrenergic receptor antagonists enable memories to be updated and rewritten when administered during consolidation and reconsolidation. Propranolol is a widely used beta-adrenergic receptor antagonist that disrupts the consolidation and reconsolidation processes of memory formation as it inhibits protein synthesis in the central nervous system. This review aims to discuss the memory impairing effect of the systemic and intracerebral administration of propranolol during the consolidation and reconsolidation processes associated with different learning tasks. In doing so, this review will help elucidate the effects of propranolol on different stages of memory formation. Since learning and maladaptive memories underpin some of the most common psychological disorders, such as phobias, post-traumatic stress disorder, addiction, drug-seeking behavior, and so on, a thorough understanding of propranolol's memory-impairing effect has significant clinical value and the potential to help people suffering from these disorders.
PubMed: 37645086
DOI: 10.29399/npa.28203 -
The Journal of Neuroscience : the... Sep 2023A well orchestrated coupling hierarchy of slow waves and spindles during slow-wave sleep supports memory consolidation. In old age, the duration of slow-wave sleep and...
A well orchestrated coupling hierarchy of slow waves and spindles during slow-wave sleep supports memory consolidation. In old age, the duration of slow-wave sleep and the number of coupling events decrease. The coupling hierarchy deteriorates, predicting memory loss and brain atrophy. Here, we investigate the dynamics of this physiological change in slow wave-spindle coupling in a frontocentral electroencephalography position in a large sample ( = 340; 237 females, 103 males) spanning most of the human life span (age range, 15-83 years). We find that, instead of changing abruptly, spindles gradually shift from being driven by slow waves to driving slow waves with age, reversing the coupling hierarchy typically seen in younger brains. Reversal was stronger the lower the slow-wave frequency, and starts around midlife (age range, ∼40-48 years), with an established reversed hierarchy between 56 and 83 years of age. Notably, coupling strength remains unaffected by age. In older adults, deteriorating slow wave-spindle coupling, measured using the phase slope index (PSI) and the number of coupling events, is associated with blood plasma glial fibrillary acidic protein levels, a marker for astrocyte activation. Data-driven models suggest that decreased sleep time and higher age lead to fewer coupling events, paralleled by increased astrocyte activation. Counterintuitively, astrocyte activation is associated with a backshift of the coupling hierarchy (PSI) toward a "younger" status along with increased coupling occurrence and strength, potentially suggesting compensatory processes. As the changes in coupling hierarchy occur gradually starting at midlife, we suggest there exists a sizable window of opportunity for early interventions to counteract undesirable trajectories associated with neurodegeneration. Evidence accumulates that sleep disturbances and cognitive decline are bidirectionally and causally linked, forming a vicious cycle. Improving sleep quality could break this cycle. One marker for sleep quality is a clear hierarchical structure of sleep oscillations. Previous studies showed that sleep oscillations decouple in old age. Here, we show that, rather, the hierarchical structure gradually shifts across the human life span and reverses in old age, while coupling strength remains unchanged. This shift is associated with markers for astrocyte activation in old age. The shifting hierarchy resembles brain maturation, plateau, and wear processes. This study furthers our comprehension of this important neurophysiological process and its dynamic evolution across the human life span.
Topics: Female; Male; Humans; Aged; Adolescent; Young Adult; Adult; Middle Aged; Aged, 80 and over; Aging; Sleep; Longevity; Sleep, Slow-Wave; Amnesia
PubMed: 37586871
DOI: 10.1523/JNEUROSCI.0586-23.2023 -
The Journal of Neuroscience : the... Oct 2023Dysfunctions in growth hormone (GH) secretion increase the prevalence of anxiety and other neuropsychiatric diseases. GH receptor (GHR) signaling in the amygdala has...
Dysfunctions in growth hormone (GH) secretion increase the prevalence of anxiety and other neuropsychiatric diseases. GH receptor (GHR) signaling in the amygdala has been associated with fear memory, a key feature of posttraumatic stress disorder. However, it is currently unknown which neuronal population is targeted by GH action to influence the development of neuropsychiatric diseases. Here, we showed that approximately 60% of somatostatin (SST)-expressing neurons in the extended amygdala are directly responsive to GH. GHR ablation in SST-expressing cells (SST mice) caused no alterations in energy or glucose metabolism. Notably, SST male mice exhibited increased anxiety-like behavior in the light-dark box and elevated plus maze tests, whereas SST females showed no changes in anxiety. Using auditory Pavlovian fear conditioning, both male and female SST mice exhibited a significant reduction in fear memory. Conversely, GHR ablation in SST neurons did not affect memory in the novel object recognition test. Gene expression was analyzed in a micro punch comprising the central nucleus of the amygdala (CEA) and basolateral (BLA) complex. GHR ablation in SST neurons caused sex-dependent changes in the expression of factors involved in synaptic plasticity and function. In conclusion, GHR expression in SST neurons is necessary to regulate anxiety in males, but not female mice. GHR ablation in SST neurons also decreases fear memory and affects gene expression in the amygdala, although marked sex differences were observed. Our findings identified for the first time a neurochemically-defined neuronal population responsible for mediating the effects of GH on behavioral aspects associated with neuropsychiatric diseases. Hormone action in the brain regulates different neurological aspects, affecting the predisposition to neuropsychiatric disorders, like depression, anxiety, and posttraumatic stress disorder. Growth hormone (GH) receptor is widely expressed in the brain, but the exact function of neuronal GH action is not fully understood. Here, we showed that mice lacking the GH receptor in a group of neurons that express the neuropeptide somatostatin exhibit increased anxiety. However, this effect is only observed in male mice. In contrast, the absence of the GH receptor in somatostatin-expressing neurons decreases fear memory, a key feature of posttraumatic stress disorder, in males and females. Thus, our study identified a specific group of neurons in which GH acts to affect the predisposition to neuropsychiatric diseases.
Topics: Female; Male; Mice; Animals; Somatostatin; Growth Hormone; Anxiety; Fear; Receptors, Somatotropin; Neurons
PubMed: 37625855
DOI: 10.1523/JNEUROSCI.0254-23.2023 -
Neurology Oct 2023The capacity of specialty memory clinics in the United States is very limited. If lower socioeconomic status or minoritized racial group is associated with reduced use... (Observational Study)
Observational Study
BACKGROUND AND OBJECTIVES
The capacity of specialty memory clinics in the United States is very limited. If lower socioeconomic status or minoritized racial group is associated with reduced use of memory clinics, this could exacerbate health care disparities, especially if more effective treatments of Alzheimer disease become available. We aimed to understand how use of a memory clinic is associated with neighborhood-level measures of socioeconomic factors and the intersectionality of race.
METHODS
We conducted an observational cross-sectional study using electronic health record data to compare the neighborhood advantage of patients seen at the Washington University Memory Diagnostic Center with the catchment area using a geographical information system. Furthermore, we compared the severity of dementia at the initial visit between patients who self-identified as Black or White. We used a multinomial logistic regression model to assess the Clinical Dementia Rating at the initial visit and tests to compare neighborhood characteristics, including Area Deprivation Index, with those of the catchment area.
RESULTS
A total of 4,824 patients seen at the memory clinic between 2008 and 2018 were included in this study (mean age 72.7 [SD 11.0] years, 2,712 [56%] female, 543 [11%] Black). Most of the memory clinic patients lived in more advantaged neighborhoods within the overall catchment area. The percentage of patients self-identifying as Black (11%) was lower than the average percentage of Black individuals by census tract in the catchment area (16%) ( < 0.001). Black patients lived in less advantaged neighborhoods, and Black patients were more likely than White patients to have moderate or severe dementia at their initial visit (odds ratio 1.59, 95% CI 1.11-2.25).
DISCUSSION
This study demonstrates that patients living in less affluent neighborhoods were less likely to be seen in one large memory clinic. Black patients were under-represented in the clinic, and Black patients had more severe dementia at their initial visit. These findings suggest that patients with a lower socioeconomic status and who identify as Black are less likely to be seen in memory clinics, which are likely to be a major point of access for any new Alzheimer disease treatments that may become available.
Topics: Aged; Female; Humans; Male; Alzheimer Disease; Black People; Cross-Sectional Studies; Racial Groups; Socioeconomic Factors; United States; Memory Disorders; White People; Neighborhood Characteristics; Middle Aged; Aged, 80 and over
PubMed: 37532510
DOI: 10.1212/WNL.0000000000207674