Hormetic effect of amyloid-beta peptide in hippocampal synaptic plasticity and memory

Background: The term hormesis refers to a biphasic dose-response phenomenon characterized by low-dose stimulation and high-dose inhibition represented by a J-shaped or U-shaped curve, depending on the parameter measured (Calabrese and Baldwin, Hum Exp Toxicol, 2002). Indeed, several, if not all, physiological molecules (i.e. glutamate, glucocorticoids, nitric oxide) are likely to present a hormetic effect, exhibiting opposite effects at high or low concentrations. In the last few years, we have focused on amyloid-beta (A), a peptide widely known because it is produced in high amounts during Alzheimer’s disease (AD). A is considered a toxic fragment causing synaptic dysfunction and memory impairment (Selkoe, Science, 2002). However, the peptide is normally produced in the healthy brain and growing evidences indicate that it might have a physiologic function. Aim: Based on previous results showing that picomolar concentrations of A42 enhance synaptic plasticity and memory (Puzzo et al, J Neurosci, 2008) and that endogenous A is necessary for synaptic plasticity and memory (Puzzo et al, Ann Neurol, 2011), the aim of our study was to demonstrate the hormetic role of A in synaptic plasticity and memory. Methods: We used 3-month old wild type mice to analyze how synaptic plasticity, measured on hippocampal slices in vitro, and spatial reference memory were modified by treatment with different doses of A (from 2 pM to 20 μM). Results: We demonstrated that A has a hormetic effect (Puzzo et al, Neurobiol Aging, 2012) with low-doses (200 pM) stimulating synaptic plasticity and memory and high-doses (≥ 200 nM) inhibiting these processes. Conclusions: Our results suggest that, paradoxically, very low doses of A might serve to enhance memory at appropriate concentrations and conditions. These findings raise several issues when designing effective and safe approaches to AD therapy.

EXPLORE THE IMPACT OF NOISE STRESS INDUCED BRAIN WAVE PATTERN AND BEHAVIOUR ALTERATIONS IN WISTAR ALBINO RATS

Objective: The aim of the study is to investigate the impact of noise-induced stress and electroencephalogram (EEG) with behavioral alteration in male Wistar albino Rats. Methods: Adult albino rats were randomly divided into three groups. Each group contains six animals. Rats exposed to acute and sub-acute noise, stress (100 dB/4 h) were compared with control animals and assessed for learning and memory using an Eight-arm radial maze, Y-maze, T-maze and also monitoring of brain electrical activity showed by the electro encephalography. Results: The reference memory and working memory error increases, in acute and sub-acute noise stress. The amplitude and frequency also increase in frontal and occipital lobar when compared to control animals. Conclusion: Animals were exposed to noise stress showed learning and memory impairment and also changes in EEG wave pattern.

Neuron-Derived Estrogen—A Key Neuromodulator in Synaptic Function and Memory

In addition to being a steroid hormone, 17β-estradiol (E2) is also a neurosteroid produced in neurons in various regions of the brain of many species, including humans. Neuron-derived E2 (NDE2) is synthesized from androgen precursors via the action of the biosynthetic enzyme aromatase, which is located at synapses and in presynaptic terminals in neurons in both the male and female brain. In this review, we discuss evidence supporting a key role for NDE2 as a neuromodulator that regulates synaptic plasticity and memory. Evidence supporting an important neuromodulatory role of NDE2 in the brain has come from studies using aromatase inhibitors, aromatase overexpression in neurons, global aromatase knockout mice, and the recent development of conditional forebrain neuron-specific knockout mice. Collectively, these studies demonstrate a key role of NDE2 in the regulation of synapse and spine density, efficacy of excitatory synaptic transmission and long-term potentiation, and regulation of hippocampal-dependent recognition memory, spatial reference memory, and contextual fear memory. NDE2 is suggested to achieve these effects through estrogen receptor-mediated regulation of rapid kinase signaling and CREB-BDNF signaling pathways, which regulate actin remodeling, as well as transcription, translation, and transport of synaptic proteins critical for synaptic plasticity and function.

Sevoflurane Promotes Neurodegeneration Through Inflammasome Formation in APP/PS1 Mice

Sevoflurane (SEVO) is a highly fluorinated methyl isopropyl ether used as an inhalational anesthetic for general anesthesia. Previous studies have shown that SEVO may induce impaired memory and recognition ability and may be associated with neurodegenerative disease, e.g., Alzheimer’s disease (AD). However, the underlying mechanism remains unknown. Here, we used a mouse AD model, APP/PS1, to study the effects of SEVO on neurodegeneration occurring in AD. We found that SEVO exposure significantly impaired the spatial reference memory, sensorimotor, and cognitive function of the mice. Mechanistically, we found that SEVO induced formation of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome and its downstream caspase 1-mediated production of IL-1β and IL-18, which subsequently deactivated brain-derived neurotrophic factor (BDNF) to promote neurodegeneration. Together, these data suggest that NLRP3 inflammasome is essential for SEVO-induced AD.

Consequences of human Tau aggregation in the hippocampal formation of ageing mice in vivo

Intracellular aggregation of hyperphosphorylated Tau (pTau) in the brain is associated with cognitive and motor impairments, and ultimately neurodegeneration. We investigate how human pTau affects cells and network activity in the hippocampal formation of THY-Tau22 tauopathy model mice in vivo. We find that pTau preferentially accumulates in deep-layer pyramidal neurons, leading to neurodegeneration, and we establish that pTau spreads to oligodendrocytes. During goal-directed virtual navigation in aged transgenic mice, we detect fewer high-firing pyramidal cells, with the remaining cells retaining their coupling to theta oscillations. Analysis of network oscillations and firing patterns of pyramidal and GABAergic neurons recorded in head-fixed and freely-moving mice suggests preserved neuronal coordination. In spatial memory tests, transgenic mice have reduced short-term familiarity but spatial working and reference memory are surprisingly normal. We hypothesize that unimpaired subcortical network mechanisms implementing cortical neuronal coordination compensate for the widespread pTau aggregation, loss of high-firing cells and neurodegeneration.

The Effects of Acute and Binge 3,4-methylenedioxymethamphetamine (MDMA) Exposure on Learning and Memory in Rats

<p>When rats are administered acute doses of MDMA they produce significantly more reference memory errors than working memory errors in the partially baited radial arm maze (Kay et al, 2009). The potential role of serotonin and dopamine in this effect was examined by administering the serotonin agonist Citalopram and the dopamine agonist GBR12909. GBR12909 produced significantly more reference memory errors, while Citalopram tended to produce more working memory errors. Administration of the D1 agonist A68930 and the D2 agonist Quinpirole predominantly produced reference memory errors, but to a lesser extent than acute MDMA administration. Low doses of both drugs produced a synergistic effect, more similar to that seen with acute MDMA administration. These findings suggest dopamine plays a role in the reference memory effect seen with MDMA exposure in the partially baited radial maze. In the second half of the thesis binge regimes of MDMA (4 x 10mg/kg) were administered to rats. When there was a gap of eight weeks between dosing and training the ability to acquire the radial arm maze was not significantly impaired. When this MDMA regime was repeated with a three-day gap between dosing and training it produced a significant but transient deficit in performance. When later challenged with acute doses of MDMA (4.0 mg/kg) the binge treated rats were less impaired than saline controls indicating drug tolerance. In an additional study that used a three-day delay between dosing and training a significant impairment in task acquisition was found. This deficit appeared to be long-term as the MDMA treated rats were impaired when the rules of task were changed suggesting a deficit in cognitive flexibility. Again when subjects were challenged with acute MDMA there was evidence of drug tolerance. The final study examined the effects of repeated MDMA exposure on task acquisition by administering acute doses of MDMA or saline once a week after rats had previously been treated with either a binge regime of MDMA or saline. MDMA exposure significantly impaired task acquisition and produced residual drug effects in the binge treated MDMA group the day after acute drug administration. However evidence of behavioural tolerance in this study was mixed due to a floor effect where performance of the binge MDMA group was so poor at the beginning of the study. In conclusion MDMA exposure impaired accuracy with reference memory processes were more affected than working memory processes. The underlying nature of this impairment remains unclear but it may be due to a long-term memory deficit, an impairment in understanding task rules or a perseverative pattern of responding. These findings imply human Ecstasy users may show deficits in acquiring information and may experience deficits in cognitive flexibility</p>

The Effects of Acute and Binge 3,4-methylenedioxymethamphetamine (MDMA) Exposure on Learning and Memory in Rats

<p>When rats are administered acute doses of MDMA they produce significantly more reference memory errors than working memory errors in the partially baited radial arm maze (Kay et al, 2009). The potential role of serotonin and dopamine in this effect was examined by administering the serotonin agonist Citalopram and the dopamine agonist GBR12909. GBR12909 produced significantly more reference memory errors, while Citalopram tended to produce more working memory errors. Administration of the D1 agonist A68930 and the D2 agonist Quinpirole predominantly produced reference memory errors, but to a lesser extent than acute MDMA administration. Low doses of both drugs produced a synergistic effect, more similar to that seen with acute MDMA administration. These findings suggest dopamine plays a role in the reference memory effect seen with MDMA exposure in the partially baited radial maze. In the second half of the thesis binge regimes of MDMA (4 x 10mg/kg) were administered to rats. When there was a gap of eight weeks between dosing and training the ability to acquire the radial arm maze was not significantly impaired. When this MDMA regime was repeated with a three-day gap between dosing and training it produced a significant but transient deficit in performance. When later challenged with acute doses of MDMA (4.0 mg/kg) the binge treated rats were less impaired than saline controls indicating drug tolerance. In an additional study that used a three-day delay between dosing and training a significant impairment in task acquisition was found. This deficit appeared to be long-term as the MDMA treated rats were impaired when the rules of task were changed suggesting a deficit in cognitive flexibility. Again when subjects were challenged with acute MDMA there was evidence of drug tolerance. The final study examined the effects of repeated MDMA exposure on task acquisition by administering acute doses of MDMA or saline once a week after rats had previously been treated with either a binge regime of MDMA or saline. MDMA exposure significantly impaired task acquisition and produced residual drug effects in the binge treated MDMA group the day after acute drug administration. However evidence of behavioural tolerance in this study was mixed due to a floor effect where performance of the binge MDMA group was so poor at the beginning of the study. In conclusion MDMA exposure impaired accuracy with reference memory processes were more affected than working memory processes. The underlying nature of this impairment remains unclear but it may be due to a long-term memory deficit, an impairment in understanding task rules or a perseverative pattern of responding. These findings imply human Ecstasy users may show deficits in acquiring information and may experience deficits in cognitive flexibility</p>

Recognition of post-learning alteration of hippocampal ripples by convolutional neural network differs in the wild-type and AD mice

Evidence indicates that sharp-wave ripples (SWRs) are primary network events supporting memory processes. However, some studies demonstrate that even after disruption of awake SWRs the animal can still learn spatial task or that SWRs may be not necessary to establish a cognitive map of the environment. Moreover, we have found recently that despite a deficit of sleep SWRs the APP/PS1 mice, a model of Alzheimer’s disease, show undisturbed spatial reference memory. Searching for a learning-related alteration of SWRs that could account for the efficiency of memory in these mice we use convolutional neural networks (CNN) to discriminate pre- and post-learning 256 ms samples of LFP signals, containing individual SWRs. We found that the fraction of samples that were correctly recognized by CNN in majority of discrimination sessions was equal to ~ 50% in the wild-type (WT) and only 14% in APP/PS1 mice. Moreover, removing signals generated in a close vicinity of SWRs significantly diminished the number of such highly recognizable samples in the WT but not in APP/PS1 group. These results indicate that in WT animals a large subset of SWRs and signals generated in their proximity may contain learning-related information whereas such information seem to be limited in the AD mice.

Temporal Alignment but not Complexity of Audiovisual Stimuli Influences Crossmodal Duration Percepts

Reliable duration perception is an integral aspect of daily life that impacts everyday perception, motor coordination, and subjective passage of time. The Scalar Expectancy Theory (SET) is a common model that explains how an internal pacemaker, gated by an external stimulus-driven switch, accumulates pulses during sensory events and compares these accumulated pulses to a reference memory duration for subsequent duration estimation. Second-order mechanisms, such as multisensory integration (MSI) and attention, can influence this model and affect duration perception. For instance, diverting attention away from temporal features could delay the switch closure or temporarily open the accumulator, altering pulse accumulation and distorting duration perception. In crossmodal duration perception, auditory signals of unequal duration can induce perceptual compression and expansion of durations of visual stimuli, presumably via auditory influence on the visual clock. The current project aimed to investigate the role of temporal (stimulus alignment) and nontemporal (stimulus complexity) features on crossmodal, specifically auditory over visual, duration perception. While temporal alignment revealed a larger impact on the strength of crossmodal duration percepts compared to stimulus complexity, both features showcase auditory dominance in processing visual duration.

Memories of Migrations Past: Sociality and Cognition in Dynamic, Seasonal Environments

Seasonal migrations are a widespread and broadly successful strategy for animals to exploit periodic and localized resources over large spatial scales. It remains an open and largely case-specific question whether long-distance migrations are resilient to environmental disruptions. High levels of mobility suggest an ability to shift ranges that can confer resilience. On the other hand, a conservative, hard-wired commitment to a risky behavior can be costly if conditions change. Mechanisms that contribute to migration include identification and responsiveness to resources, sociality, and cognitive processes such as spatial memory and learning. Our goal was to explore the extent to which these factors interact not only to maintain a migratory behavior but also to provide resilience against environmental changes. We develop a diffusion-advection model of animal movement in which an endogenous migratory behavior is modified by recent experiences via a memory process, and animals have a social swarming-like behavior over a range of spatial scales. We found that this relatively simple framework was able to adapt to a stable, seasonal resource dynamic under a broad range of parameter values. Furthermore, the model was able to acquire an adaptive migration behavior with time. However, the resilience of the process depended on all the parameters under consideration, with many complex trade-offs. For example, the spatial scale of sociality needed to be large enough to capture changes in the resource, but not so large that the acquired collective information was overly diluted. A long-term reference memory was important for hedging against a highly stochastic process, but a higher weighting of more recent memory was needed for adapting to directional changes in resource phenology. Our model provides a general and versatile framework for exploring the interaction of memory, movement, social and resource dynamics, even as environmental conditions globally are undergoing rapid change.