Reduction In Synaptic Density Research Articles

Depression in older adults and its associations with sleep and synaptic density

BackgroundDepression among older adults is a global concern, contributing to disability and overall illness burden. Understanding its trajectory, associated risk factors, and implications for mortality is essential for effective intervention. Moreover, the relationship between depression, sleep disturbances, and synaptic density in the ageing brain remains complex and poorly understood. MethodsUsing data from the University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age cohort, comprising 6375 participants, we conducted comprehensive assessments of depression trajectories using generalized linear mixed models and mortality risks using Cox mixed-effects models. Generalized structural equation modelling was performed to explore longitudinal associations between sleep duration and depression. Lastly, associations between post-mortem synaptic density and depression were investigated. ResultsOur findings revealed that depression rates declined until age 80 before increasing again. Depression was associated with a 10 % increased risk of mortality in older adults. Reduced sleep was correlated with depression, and depression measured early in the study predicted future reduced sleep. Post-mortem analysis showed a global reduction in synaptic density associated with depression, particularly pronounced in the frontal lobe. LimitationsLimitations include recall bias, limiting generalizability due to dominantly including White British participants and difficulty in establishing causation between synaptic density and depression. ConclusionOur study underscores the significance of addressing depression in older adults, not only for mental health but also for mortality risk and neurobiological health. Early detection and intervention strategies are crucial for improving outcomes in elderly populations, potentially mitigating adverse effects on sleep, synaptic density, cognitive health, and longevity.

Effects of Mild Closed-Head Injury and Subanesthetic Ketamine Infusion on Microglia, Axonal Injury, and Synaptic Density in Sprague-Dawley Rats.

Mild traumatic brain injury (mTBI) affects millions of people in the U.S. Approximately 20-30% of those individuals develop adverse symptoms lasting at least 3 months. In a rat mTBI study, the closed-head impact model of engineered rotational acceleration (CHIMERA) produced significant axonal injury in the optic tract (OT), indicating white-matter damage. Because retinal ganglion cells project to the lateral geniculate nucleus (LGN) in the thalamus through the OT, we hypothesized that synaptic density may be reduced in the LGN of rats following CHIMERA injury. A modified SEQUIN (synaptic evaluation and quantification by imaging nanostructure) method, combined with immunofluorescent double-labeling of pre-synaptic (synapsin) and post-synaptic (PSD-95) markers, was used to quantify synaptic density in the LGN. Microglial activation at the CHIMERA injury site was determined using Iba-1 immunohistochemistry. Additionally, the effects of ketamine, a potential neuroprotective drug, were evaluated in CHIMERA-induced mTBI. A single-session repetitive (ssr-) CHIMERA (3 impacts, 1.5 joule/impact) produced mild effects on microglial activation at the injury site, which was significantly enhanced by post-injury intravenous ketamine (10 mg/kg) infusion. However, ssr-CHIMERA did not alter synaptic density in the LGN, although ketamine produced a trend of reduction in synaptic density at post-injury day 4. Further research is necessary to characterize the effects of ssr-CHIMERA and subanesthetic doses of intravenous ketamine on different brain regions and multiple time points post-injury. The current study demonstrates the utility of the ssr-CHIMERA as a rodent model of mTBI, which researchers can use to identify biological mechanisms of mTBI and to develop improved treatment strategies for individuals suffering from head trauma.

Decreased Synaptic Vesicle Glycoprotein 2A Binding in the Human Postmortem Essential Tremor Cerebellum: Evidence of Reduction in Synaptic Density.

Despite being one of the most prevalent neurological diseases, the pathophysiology of essential tremor (ET) is not fully understood. Neuropathological studies have identified numerous degenerative changes in the cerebellum of ET patients, however. These data align with considerable clinical and neurophysiological data linking ET to the cerebellum. While neuroimaging studies have variably shown mild atrophy in the cerebellum, marked atrophy is not a clear feature of the cerebellum in ET and a search for a more suitable neuroimaging signature of neurodegeneration is in order. Postmortem studies in ET have examined different neuropathological alterations in the cerebellum, but as of yet have not focused on measures of generalized synaptic markers. This pilot study focuses on synaptic vesicle glycoprotein 2A (SV2A), a protein expressed in practically all synapses in the brain, as a measure of synaptic density in postmortem ET cases. The current study utilized autoradiography with the SV2A radioligand [18F]SDM-16 to assess synaptic density in the cerebellar cortex and dentate nucleus in three ET cases and three age-matched controls. Using [18F]SDM-16, SV2A was 53% and 46% lower in the cerebellar cortex and dentate nucleus, respectively, in ET cases compared to age-matched controls. In this pilot study, using in vitro SV2A autoradiography, we have observed significantly lower synaptic density in the cerebellar cortex and dentate nucleus of ET cases. Future research could expand on our sample size and focus on in vivo imaging in ET to explore whether SV2A imaging could serve as a much-needed disease biomarker.

Neurophysiological consequences of synapse loss in progressive supranuclear palsy.

Synaptic loss occurs early in many neurodegenerative diseases and contributes to cognitive impairment even in the absence of gross atrophy. Currently, for human disease there are few formal models to explain how cortical networks underlying cognition are affected by synaptic loss. We advocate that biophysical models of neurophysiology offer both a bridge from preclinical to clinical models of pathology and quantitative assays for experimental medicine. Such biophysical models can also disclose hidden neuronal dynamics generating neurophysiological observations such as EEG and magnetoencephalography. Here, we augment a biophysically informed mesoscale model of human cortical function by inclusion of synaptic density estimates as captured by 11C-UCB-J PET, and provide insights into how regional synapse loss affects neurophysiology. We use the primary tauopathy of progressive supranuclear palsy (Richardson's syndrome) as an exemplar condition, with high clinicopathological correlations. Progressive supranuclear palsy causes a marked change in cortical neurophysiology in the presence of mild cortical atrophy and is associated with a decline in cognitive functions associated with the frontal lobe. Using parametric empirical Bayesian inversion of a conductance-based canonical microcircuit model of magnetoencephalography data, we show that the inclusion of regional synaptic density-as a subject-specific prior on laminar-specific neuronal populations-markedly increases model evidence. Specifically, model comparison suggests that a reduction in synaptic density in inferior frontal cortex affects superficial and granular layer glutamatergic excitation. This predicted individual differences in behaviour, demonstrating the link between synaptic loss, neurophysiology and cognitive deficits. The method we demonstrate is not restricted to progressive supranuclear palsy or the effects of synaptic loss: such pathology-enriched dynamic causal models can be used to assess the mechanisms of other neurological disorders, with diverse non-invasive measures of pathology, and is suitable to test the effects of experimental pharmacology.

Synaptic loss and gliosis in the nucleus tractus solitarii with streptozotocin-induced Alzheimer’s disease

Obstructive sleep apnea is highly prevalent in Alzheimer’s disease (AD). However, brainstem centers controlling respiration have received little attention in AD research, and mechanisms behind respiratory dysfunction in AD are not understood. The nucleus tractus solitarii (nTS) is an important brainstem center for respiratory control and chemoreflex function. Alterations of nTS integrity, like those shown in AD patients, likely affect neuronal processing and adequate control of breathing. We used the streptozotocin-induced rat model of AD (STZ-AD) to analyze cellular changes in the nTS that corroborate previously documented respiratory dysfunction. We used 2 common dosages of STZ (2 and 3 mg/kg STZ) for model induction and evaluated the early impact on cell populations in the nTS. The hippocampus served as control region to identify site-specific effects of STZ. There was significant atrophy in the caudal nTS of the 3 mg/kg STZ-AD group only, an area known to integrate chemoafferent information. Also, the hippocampus had significant atrophy with the highest STZ dosage tested. Both STZ-AD groups showed respiratory dysfunction along with multiple indices for astroglial and microglial activation. These changes were primarily located in the caudal and intermediate nTS. While there was no change of astrocytes in the hippocampus, microglial activation was accompanied by a reduction in synaptic density. Together, our data demonstrate that STZ-AD induces site-specific effects on all major cell types, primarily in the caudal/intermediate nTS. Both STZ dosages used in this study produced a similar outcome and can be used for future studies examining the initial symptoms of STZ-AD.

Imaging synaptic density in depression.

Major depressive disorder is a prevalent and heterogeneous disorder with treatment resistance in at least 50% of individuals. Most of the initial studies focused on the monoamine system; however, recently other mechanisms have come under investigation. Specific to the current issue, studies show synaptic involvement in depression. Other articles in this issue report on reductions in synaptic density, dendritic spines, boutons and glia associated with stress and depression. Importantly, it appears that some drugs (e.g., ketamine) may lead to rapid synaptic restoration or synaptogenesis. Direct evidence for this comes from preclinical work. However, neuroimaging studies, such as magnetic resonance imaging (MRI) and positron emission tomography (PET), have become useful in assessing these changes in vivo. Here, we describe the use of neuroimaging techniques in the evaluation of synaptic alterations associated with depression in humans, as well as measurement of synaptic restoration after administration of ketamine. Although more research is desired, use of these techniques widen our understanding of depression and move us further along the path to targeted and effective treatment for depression.

Electroacupuncture Ameliorates Depression-Like Behaviour in Rats by Enhancing Synaptic Plasticity via the GluN2B/CaMKII/CREB Signalling Pathway.

Background Hippocampal synaptic plasticity during the pathological process of depression has received increasing attention. Hippocampal neuron atrophy and the reduction in synaptic density induced by chronic stress are important pathological mechanisms of depression. Electroacupuncture (EA) exerts beneficial effects on depression, but the mechanism is unclear. This study explored the effect of EA on synaptic plasticity and the potential mechanism. Methods Forty-eight SD rats were randomly divided into the control, chronic unpredictable mild stress (CUMS), EA, and fluoxetine (FLX) groups, and each group consisted of 12 rats. The sucrose preference test, open field test, and forced swimming test were used for the evaluation of depression-like behaviour, and Golgi and Nissl staining were used for the assessment of synaptic plasticity. Western blotting and immunofluorescence were conducted to detect proteins related to synaptic plasticity and to determine their effects on signalling pathways. Results We found that CUMS led to depression-like behaviours, including a reduced preference for sucrose, a prolonged immobility time, and reduced exploration activity. The dendritic spine densities and neuron numbers and the protein levels of MAP-2, PSD-95, and SYN were decreased in the hippocampi of rats with CUMS-induced depression, and these trends were reversed by EA. The molecular mechanism regulating this plasticity may involve the GluN2B/CaMKII/CREB signalling pathway. Conclusion These results suggest that EA can improve depression-like behaviour and hippocampal plasticity induced by CUMS, and the mechanism may be related to the GluN2B/CaMKII/CREB pathway.

In vivo coupling of dendritic complexity with presynaptic density in primary tauopathies

Understanding the cellular underpinnings of neurodegeneration remains a challenge; loss of synapses and dendritic arborization are characteristic and can be quantified in vivo, with [11C]UCB-J PET and MRI-based Orientation Dispersion Imaging (ODI), respectively. We aimed to assess how both measures are correlated, in 4R-tauopathies of progressive supranuclear palsy – Richardson's Syndrome (PSP-RS; n = 22) and amyloid-negative (determined by [11C]PiB PET) Corticobasal Syndrome (Cortiobasal degeneration, CBD; n =14), as neurodegenerative disease models, in this proof-of-concept study. Compared to controls (n = 27), PSP-RS and CBD patients had widespread reductions in cortical ODI, and [11C]UCB-J non-displaceable binding potential (BPND) in excess of atrophy. In PSP-RS and CBD separately, regional cortical ODI was significantly associated with [11C]UCB-J BPND in disease-associated regions (p < 0.05, FDR corrected). Our findings indicate that reductions in synaptic density and dendritic complexity in PSP-RS and CBD are more severe and extensive than atrophy. Furthermore, both measures are tightly coupled in vivo, furthering our understanding of the pathophysiology of neurodegeneration, and applicable to studies of early neurodegeneration with a safe and widely available MRI platform.

Association between cerebral amyloid accumulation and synaptic density in Alzheimer’s disease: A multitracer PET study

AbstractBackgroundSynaptic loss is an early pathology in Alzheimer’s disease (AD) and the major structural correlate of cognitive impairment. We have recently demonstrated extensive synaptic loss in medial temporal and neocortical brain regions of participants with AD. In this study, we further investigate the association of global and local amyloid burden with synaptic density in AD using [11C]UCB‐J PET.Method[11C]UCB‐J and [11C]PiB binding were measured in 38 participants with AD and 19 cognitively normal participants aged 55‐85 years. For [11C]PiB analysis, parametric images of binding potential (BPND ) were generated using SRTM2 with cerebellum as a reference region and converted to distribution volume ratios (DVR). For [11C]UCB‐J, BPND was computed using SRTM2 with a shrunken centrum semiovale reference region and converted to DVR with a cerebellum reference region.ResultThe AD group showed significant widespread reductions in cortical and subcortical synaptic density, most pronounced in medial temporal lobe, and significantly elevated cortical amyloid in regions commonly affected by AD pathology (Figure 1). Among pooled participants (n=57), higher global amyloid burden was associated with lower synaptic density in the majority of regions. Significant negative associations between local amyloid and SV2A were also observed across the majority of cortical regions in the pooled sample (lateral temporal, prefrontal, posterior cingulate/precuneus, lateral parietal, and lateral occipital; r=‐0.29 to ‐0.48, p&lt;0.05) with the exception of medial temporal (r=‐0.18, p=0.17), anterior cingulate (r=‐0.19, p=0.15), and pericentral (r=‐0.23, p=0.08) cortices (Figure 2). These significant associations between either global or regional amyloid and SV2A were not observed in analyses restricted to the AD group, in both an region‐ or surface‐based analysis (Figure 3).ConclusionUsing [11C]UCB‐J PET, widespread reductions of synaptic density were observed in AD participants. Cortical regions associated with the least accumulation of fibrillar amyloid (medial temporal lobe) were associated with the most pronounced reductions in synaptic density. Significant negative associations between both global and local amyloid and synaptic density in the pooled sample were driven by group differences, and not significant within the AD group alone. Our findings are consistent with postmortem studies describing the patterns of fibrillar amyloid burden and synaptic loss in AD.

OPA1 deficiency accelerates hippocampal synaptic remodelling and age-related deficits in learning and memory.

A healthy mitochondrial network is essential for the maintenance of neuronal synaptic integrity. Mitochondrial and metabolic dysfunction contributes to the pathogenesis of many neurodegenerative diseases including dementia. OPA1 is the master regulator of mitochondrial fusion and fission and is likely to play an important role during neurodegenerative events. To explore this, we quantified hippocampal dendritic and synaptic integrity and the learning and memory performance of aged Opa1 haploinsufficient mice carrying the Opa1Q285X mutation (B6; C3-Opa1Q285STOP; Opa1+/−). We demonstrate that heterozygous loss of Opa1 results in premature age-related loss of spines in hippocampal pyramidal CA1 neurons and a reduction in synaptic density in the hippocampus. This loss is associated with subtle memory deficits in both spatial novelty and object recognition. We hypothesize that metabolic failure to maintain normal neuronal activity at the level of a single spine leads to premature age-related memory deficits. These results highlight the importance of mitochondrial homeostasis for maintenance of neuronal function during ageing.

ASSOCIATION BETWEEN CEREBRAL AMYLOID ACCUMULATION AND SYNAPTIC DENSITY IN ALZHEIMER'S DISEASE: A MULTITRACER PET STUDY

Introduction Alzheimer's Disease (AD) pathology is traditionally characterized by the accumulation of extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles comprised of hyperphosphorylated tau. However, an equally important pathology, synaptic loss, has been demonstrated to be an early event in the disease process and a major structural correlate of cognitive impairment. Recently, positron emission tomography (PET) imaging of synaptic vesicle glycoprotein 2A (SV2A) has emerged as a novel biomarker of synaptic density. We have previously demonstrated extensive synaptic loss that is more widespread than reductions in gray matter volume in cortical and subcortical brain regions of participants with AD. The current study further investigates the association of local and global cortical amyloid burden with synaptic density. Methods [11C]UCB-J binding to SV2A and [11C]PiB binding to amyloid were measured in 38 participants with AD (14 amnestic MCI and 24 mild dementia) and 20 cognitively normal (CN) participants aged 55-85?years. For [11C]PiB image analysis, parametric images of the binding potential (BPND) were generated using SRTM2 with whole cerebellum as a reference region and converted to distribution volume ratios (DVR). For [11C]UCB-J, parametric images of BPND were first computed using SRTM2 with a shrunken (2 mL) centrum semiovale (CS) reference region. BPND was then converted to DVR with a cerebellum reference region. Brain amyloid and synaptic density were measured in frontal, posterior cingulate/precuneus, lateral parietal, lateral temporal, medial temporal, lateral occipital, medial occipital, and pericentral regions of interest (ROIs). For [11C]PiB parametric images, a composite cortical DVR (representative of global amyloid burden) was calculated by combining the frontal, posterior cingulate/precuneus, lateral parietal, and lateral temporal regions. Results The study sample consisted of 58 participants (38 AD and 20 CN) with no group differences observed in sex (p=0.85), age (p=0.46), or education (p=0.06). AD participants had clinical characteristics typical of amnestic MCI and mild AD with CDR-global = 0.74±0.25 (p Conclusions Using [11C]UCB-J PET, widespread reductions of synaptic density in cortical and subcortical regions were observed in AD compared to CN participants. This included regions not traditionally associated with fibrillar amyloid pathology, such as the pericentral cortex. Interestingly, the cortical regions associated with the least robust accumulation of fibrillar amyloid (medial temporal cortex) were associated with the most pronounced reductions in synaptic density. Although significant negative associations between both global and local amyloid burden and regional synaptic density were observed for the pooled sample, this was driven by differences between diagnostic groups and was not significant within the AD group alone. Our findings are therefore consistent with previous postmortem studies describing the patterns of fibrillar amyloid burden and synaptic loss in AD. This research was funded by: NIA (P50AG047270 [CHvD], K23AG057784 [APM], R01AG052560 [REC, CHV], R01AG062276 [CHvD], and The Dana Foundation [MKC]), NIMH R25MH071584 and T32MH019961 (RSO), and the Detre T. Memorial Fellowship (RSO).

Complement-dependent synapse loss and microgliosis in a mouse model of multiple sclerosis

Multiple sclerosis (MS) is an inflammatory, neurodegenerative disease of the CNS characterized by both grey and white matter injury. Microglial activation and a reduction in synaptic density are key features of grey matter pathology that can be modeled with MOG35-55 experimental autoimmune encephalomyelitis (EAE). Complement deposition combined with microglial engulfment has been shown during normal development and in disease as a mechanism for pruning synapses. We tested whether there is excess complement production in the EAE hippocampus and whether complement-dependent synapse loss is a source of degeneration in EAE using C1qa and C3 knockout mice. We found that C1q and C3 protein and mRNA levels were elevated in EAE mice. Genetic loss of C3 protected mice from EAE-induced synapse loss, reduced microglial activation, decreased the severity of the EAE clinical score, and protected memory/freezing behavior after contextual fear conditioning. C1qa KO mice with EAE showed little to no change on these measurements compared to WT EAE mice. Thus, pathologic expression and activation of the early complement pathway, specifically at the level of C3, contributes to hippocampal grey matter pathology in the EAE.

P: 76 Reversible and Irreversible Neurological Complications in Hepatic Encephalopathy

BACKGROUND: Hepatic encephalopathy (HE) is a major neurological condition that occurs due to acute and chronic liver failure following drug toxicity, viral hepatitis, or exposure to various hepatotoxins. Acute HE (Type A HE) is associated with cerebral edema, increased intracranial pressure, coma and death. Chronic HE (Type C HE) is characterized by mental confusion, behavioral changes, and motor disturbances. It is currently unclear whether HE is reversible or irreversible. We therefore examined whether acute or chronic liver failure is reversible or irreversible in the thioacetamide (TAA) rat model of acute and chronic HE. Accordingly, rats were treated with the liver toxin TAA and brain edema, neurobehavioral, cognitive and motor deficits were measured. METHODS: Rats were treated with the liver toxin TAA and brain edema, neurobehavioral, cognitive and motor deficits were measured. RESULTS: Treatment of rats with high doses of TAA (to induce acute HE) led to brain edema within 2-3 days. Rats following TAA treatment were examined for longer time-periods. Rats did not exhibit any brain edema, although they expressed neurobehavioral, cognitive and motor deficits without any changes documented in blood and brain ammonia levels, as well as liver failure markers, as compared to normal rats. However, rats that underwent chronic liver failure for 10 days displayed neurobehavioral, cognitive and motor deficits, along with brain structural and molecular events, including reduced levels of astrocytic matricellular proteins, as well as reduced levels of neuronal proteins. We also found a reduction in synaptic density and in dendritic complexity. These changes correlated-well with increased blood/brain ammonia levels and with liver failure markers. However, when TAA treatment was withdrawn (after 10 days), and the rats monitored for longer time periods still showed neurobehavioral, cognitive and motor deficits, as well as defective neuronal integrity, even though blood and brain ammonia levels, as well as liver biochemical and molecular parameters were reversed. CONCLUSIONS: These findings strongly suggest that neurobehavioral, cognitive and motor deficits in HE cannot be reversed even when acute or chronic liver failure had been corrected.

HIV Tat causes synapse loss in a mouse model of HIV-associated neurocognitive disorder that is independent of the classical complement cascade component C1q.

Microglial activation, increased proinflammatory cytokine production, and a reduction in synaptic density are key pathological features associated with HIV-associated neurocognitive disorders (HAND). Even with combination antiretroviral therapy (cART), more than 50% of HIV-positive individuals experience some type of cognitive impairment. Although viral replication is inhibited by cART, HIV proteins such as Tat are still produced within the nervous system that are neurotoxic, involved in synapse elimination, and provoke enduring neuroinflammation. As complement deposition on synapses followed by microglial engulfment has been shown during normal development and disease to be a mechanism for pruning synapses, we have tested whether complement is required for the loss of synapses that occurs after a cortical Tat injection mouse model of HAND. In Tat-injected animals evaluated 7 or 28 days after injection, levels of early complement pathway components, C1q and C3, are significantly elevated and associated with microgliosis and a loss of synapses. However, C1qa knockout mice have the same level of Tat-induced synapse loss as wild-type (WT) mice, showing that the C1q-initiated classical complement cascade is not driving synapse removal during HIV1 Tat-induced neuroinflammation.

Widespread synaptic loss in multiple sclerosis.

This scientific commentary refers to ‘Reconstruction of single cortical projection neurons reveals primary spine loss in multiple sclerosis’, by Jurgens et al. (doi:10.1093/brain/awv353). It has been estimated that the human brain comprises 8.6 × 1011 neurons that are connected by ∼1014 synapses (Pakkenberg et al. , 2003). These synapses decline in number during ageing and show accelerated loss in neurodegenerative diseases such as Alzheimer’s disease (Selkoe, 2002). However, whether synaptic loss also occurs in multiple sclerosis and, if so, how it relates to demyelination and axonal input, is unclear. In this issue of Brain , Jurgens et al. use elegant staining and imaging techniques to shed light on synaptic pathology in multiple sclerosis, and conclude that such pathology is widespread and occurs without coincident demyelination or axonal degeneration (Jurgens et al. , 2016). While multiple sclerosis was initially considered to be a chronic inflammatory disease that mainly affects white matter, it is now clear that grey matter pathology such as neuronal and axonal loss is equally widespread (Friese et al. , 2014). Demyelinated areas in the hippocampi of multiple sclerosis brains show a consistent reduction in synaptic density (Dutta et al. , 2011). Grey matter demyelination and accompanying neuronal demise contribute to permanent neurological disability in multiple sclerosis as revealed by their correlation with disease progression (Calabrese et al. , 2013). Similarly, cognitive dysfunction is found in over 50% of patients with multiple sclerosis and can be attributed to grey matter pathology (Chiaravalloti and DeLuca, 2008). While all neuronal subcellular structures are affected …

Memory, emotion, and age: the work of kinugawa et Al. (2013).

Memory is the key to our life. Already in 1870, the famous physiologist Hering (1) stated in a booklet that memory “connects innumerable single phenomena into a whole, and just as the body would be scattered like dust in countless atoms if the attraction of matter did not hold it together so consciousness – without the connecting power of memory – would fall apart in as many fragments as it contains moments” (p. 12; my translation). With this statement, he emphasized that healthy human beings are able to mentally travel in time and that in their presence they can learn from their past to find optimal solutions for their future. It is known that this capacity needs time, brain maturation, and the establishment of an autonomous self (including theory of mind abilities and the ability to show empathy) in order to develop and persist (2). Adults consequently cannot consciously remember events that had occurred prior to the age of 3–4 years (3–6). On the other hand, in dementia the ability to travel back in time deteriorates and then gets lost totally (7). The deterioration of episodic–autobiographical memory [cf. the Figure in Ref. (8), or Figure 3 in Ref. (9)] is accompanied by a reduction in emotional colorization of retrieved events – the descriptions become more fact-like, are less detailed, and are reproduced without corresponding affect (10) (Figure ​(Figure1).1). The reduced emotional impact on behavior in old people extends to a number of everyday situations (11) and may lead to retrieval deficits especially in situations guiding retrieval. Figure 1 Production of semantic and episodic–autobiographical details in patients with mild cognitive impairment (MCI), mild to moderate Alzheimer’s disease (AD mild/moderate), and severe Alzheimer’s disease (AD severe). Data from Seidl ... The interaction between memory and emotion across the life span was the topic of a nicely designed experiment by Kinugawa et al. (12). A “what, where, and when” paradigm was used that allowed measuring content and temporal and spatial context of an event by combining the presentation of visual scenes with a context story with an emotionally arousing content. Participants were divided into three groups of 17, 16, and 8 volunteers with mean ages of 27, 55, and 79 years, and tested with this paradigm. The principal outcome was that the old compared to the young group was poorer in recall and had in addition a lower working memory performance and less anxiety as measured by state and trait anxiety scales. These results add to a number of related ones, demonstrating that older people recruit more brain regions to perform a given task (13), have a less sharp differentiation between explicit and implicit memory processing (14), and perceive life processes as speeding up with age (15). Furthermore, it was found that old people have a higher tendency to forget negative emotional memories, compared to positive or neutral ones (16). Already in the year 2005, Drachman (17) in an editorial highlighted the manifold brain changes in the elderly (e.g., neuronal loss, white matter loss, volume shrinkage, sulcal widening, reduction of synaptic density), which probably account for the intellectual decline found with increasing age. Drachman wrote: “Using the standard age correction for the Wechsler Adult Intelligence Scale (WAIS), to obtain an IQ score of 100 at age 75, one need to answer only half as many questions correctly as at age 21!” (p. 2005). Though the neuronal and intellectual decline may not be universal (18), it still affects the great majority of old people (19). Conventional mental training may be a much less effective counteractive treatment (20) than physical exercise (21, 22). The new episodic memory task proposed by Kinugawa et al. might nevertheless be apt to induce new attempts not only to assess, but also to train memory in older people. The authors themselves suggest a number of possible approaches for future research in this direction.

Myosin II regulates actin rearrangement-related structural synaptic plasticity during conditioned taste aversion memory extinction

Similar to memory formation, memory extinction is also a new learning process that requires synaptic plasticity. Actin rearrangement is fundamental for synaptic plasticity, however, whether actin rearrangement in the infralimbic cortex (IL) plays a role in memory extinction, as well as the mechanisms underlying it, remains unclear. Here, using a conditioned taste aversion (CTA) paradigm, we demonstrated increased synaptic density and actin rearrangement in the IL during the extinction of CTA. Targeted infusion of an actin rearrangement inhibitor, cytochalasin D, into the IL impaired memory extinction and de novo synapse formation. Notably, we also found increased myosin II phosphorylation in the IL during the extinction of CTA. Microinfusion of a specific inhibitor of the myosin II ATPase, blebbistatin (Blebb), into the IL impaired memory extinction as well as the related actin rearrangement and changes in synaptic density. Moreover, the extinction deficit and the reduction of synaptic density induced by Blebb could be rescued by the actin polymerization stabilizer jasplakinolide (Jasp), suggesting that myosin II acts via actin filament polymerization to stabilize synaptic plasticity during the extinction of CTA. Taken together, we conclude that myosin II may regulate the plasticity of actin-related synaptic structure during memory extinction. Our studies provide a molecular mechanism for understanding the plasticity of actin rearrangement-associated synaptic structure during memory extinction.

Age-Induced Loss of Mossy Fibre Synapses on CA3 Thorns in the CA3 Stratum Lucidum.

Advanced ageing is associated with hippocampal deterioration and mild cognitive decline. The hippocampal subregion CA3 stratum lucidum (CA3-SL) receives neuronal inputs from the giant mossy fibre boutons of the dentate gyrus, but relatively little is known about the integrity of this synaptic connection with ageing. Using serial electron microscopy and unbiased stereology, we examined age-related changes in mossy fibre synapses on CA3 thorny excrescences within the CA3-SL of young adults (4-month-old), middle-aged (12-month-old), and old-aged (28-month-old) Wistar rats. Our data show that while there is an increase in CA3 volume with ageing, there is a significant (40–45%) reduction in synaptic density within the CA3-SL of 12- and 28-month-old animals compared with 4-month-old animals. We also present preliminary data showing that the CA3 neuropil in advanced ageing was conspicuously full of lipofuscin and phagolysosome positive, activated microglial cellular processes, and altered perivascular pathology. These data suggest that synaptic density in the CA3-SL is significantly impaired in ageing, accompanied by underlying prominent ultrastructural glial and microvascular changes.

FcgRIIb mediates amyloid-β neurotoxicity and memory impairment in a model of Alzheimer’s disease

Amyloid-β (Aβ) induces neuronal loss and cognitive deficits and is believed to be a prominent cause of Alzheimer’s disease (AD). However, the cellular mechanism of the pathogenesis is not fully understood. Here we report that Fcg-receptor IIb (FcgRIIb) mediates Aβ neurotoxicity and neurodegeneration. We found that FcgRIIb is significantly up-regulated in the hippocampus of AD brains and neuronal cells exposed to Aβ1-42. Neuronal FcgRIIb activates ER stress and caspase-12, and FcgRIIb knockout primary neurons are resistant to Aβ1-42-induced cell death in vitro. FcgRIIb deficiency ameliorates Aβ1-42-induced inhibition of long-term potentiation and inhibits the reduction of synaptic density by naturally secreted Aβ. Moreover, genetic depletion of FcgRIIb rescues the memory impairments in AD model mice. In an action mode of FcgRIIb in Aβ neurotoxicity, we found that soluble Aβ1-42 oligomers interact with FcgRIIb in vitro and in AD brains, and inhibition of their interaction blocks Aβ1-42 neurotoxicity. Thus, we conclude that FcgRIIb has an aberrant but essential role in Aβ1-42-mediated neuronal dysfunction, providing insight into Aβ neuropathology.

Fortress Brain

Neurodegenerative diseases are associated with neuronal inclusions, comprised of protein aggregates. In Alzheimer’s Disease (AD) and Lewy Body Disease (LBD) such lesions are distributed in a hierarchical retrograde transynaptic spatial pattern. This implies a retrograde transynaptic temporal propagation as well. There can be few explanations for this other than infectious agents (prions and viruses). This suggests that AD and LBD (at least) may have infectious origins.Transynaptic infiltration of the CNS along cranial nerve or other major projections, by one or more infectious agents has important implications. The clinical syndrome and natural history of each neurodegenerative disorder will reflect its portal of entry. There may be a different neurodegenerative syndrome for each cranial nerve or other portal of entry, and not all may manifest as “dementia”. Each syndrome may be associated with more than one pathological lesion. Each pathology may be associated with several clinical syndromes.Host-parasite interactions are species specific. This may explain the rarity of AD-like pathology in most other older mammals. Over evolutionary timescales, the human brain should be adapted to predation by neurotropic agents. Viewed from this perspective, the prion-like pro-inflammatory and pro-apoptotic properties of β-amyloid and other proteins may be adaptive, and anti-microbial. Reductions in synaptic density may slow the progress of invading pathogens, while perineuronal nets and other structures may guard the gates. This suggests a defense in depth of a structure, the brain, that is inherently vulnerable to invasion along its neural networks.