Modelling depression in animals and the potential antidepressant effect of histaminergic modulation

Depression is at the top position for "years lived with disability" (Smith, 2014). Its aetiology is unknown, but the pathogenesis implicates changes in glutamatergic neuronal plasticity. Glutamatergic plasticity likely mediates the effects of antidepressants acting through monoamines. Histamine is a monoaminergic neuromodulator able to regulate glutamatergic plasticity and synaptic transmission. The Flinders sensitive line (FSL) rat has face and predictive validity as model of depression when using traditional behavioural tests. However, these tests are usually missing complex explorative strategies that the animal performs in novel situations and that may be a relevant feature for a model of depression. We aimed to profile the FSL rat in terms of explorative strategies and coping styles displayed in a novel environment. The multivariate concentric square field™ (MCSF) consists of zones with different degrees of aversion. In the MCSF test, FSL rats showed lower exploratory drive, less recurrence to the shelter, and more risk assessment compared to Sprague Dawley rats, but no difference in risk-taking behaviours. In the novel cage test (consisting in a new bare environment) and in the home cage change test (to measure social behaviours), the FSL rat displayed a reactive coping style, described by immobility and lower aggression compared to Sprague Dawley rats. This profile shows similarities with temperaments and coping styles related to depression. Depression is linked to alteration of glutamatergic plasticity and similar alterations have been found in the hippocampus of FSL rats. Histamine H3 receptor (H3R) antagonists have displayed antidepressant properties in preclinical studies. We assessed the antidepressant properties of the H3R antagonist, clobenpropit, and its effect on hippocampal glutamatergic transmission in FSL rats. In the forced swim test, both systemic and hippocampal injections of clobenpropit reduced the immobility time. Clobenpropit improved memory in the novel object recognition and passive avoidance tests, with no effect on anxiety-related tests. Clobenpropit applied on hippocampal slices enhanced long-term synaptic potentiation (LTP), and, accordingly, in vivo administration increased the hippocampal levels of the NMDA receptor subunit GluN2A. Clobenpropit's effects both in the forced swim test and on LTP were prevented by blocking the hippocampal H1 and H2 receptors. In summary, clobenpropit exhibits antidepressant properties and regulates hippocampal glutamatergic plasticity, likely by an increase of histamine release and subsequent activation of the H1 and H2 receptors. Histamine receptors trigger intracellular signalling involved in the regulation of glutamatergic synaptic receptors, a mechanism that can affect synaptic strength. We assessed the histaminergic modulation of glutamatergic synaptic strength by recording miniature excitatory postsynaptic currents (mEPSCs) from CA1 pyramidal neurons in hippocampal slices from Sprague Dawley rats. The H1R, but not the H2R, agonist reduced mEPSC frequency, with no change of amplitude, suggesting a reduction of vesicle release probability. However, the paired-pulse facilitation (a measure of presynaptic release probability) was not altered by either the H1R or the H2R agonist, possibly due to a differential modulation of evoked versus spontaneous vesicle release. However, a postsynaptic origin of mEPSC frequency reduction cannot be excluded

Electrophysiological evidence for memory schemas in the rat hippocampus

According to Piaget and Bartlett, learning involves both assimilation of new memories into networks of preexisting knowledge and alteration of existing networks to accommodate new information into existing schemas. Recent evidence suggests that the hippocampus integrates related memories into schemas that link representations of separately acquired experiences. In this thesis, I first review models for how memories of individual experiences become consolidated into the structure of world knowledge. Disruption of consolidated memories can occur during related learning, which suggests that consolidation of new information is the reconsolidation of related memories. The accepted role of the hippocampus during memory consolidation and reconsolidation suggests that it is also involved in modifying appropriate schemas during learning. To study schema development, I trained rats to retrieve rewards at different loci on a maze while recording hippocampal calls. About a quarter of cells were active at multiple goal sites, though the ensemble as a whole distinguished goal loci from one another. When new goals were introduced, cells that had been active at old goal locations began firing at the new locations. This initial generalization decreased in the days after learning. Learning also caused changes in firing patterns at well-learned goal locations. These results suggest that learning was supported by modification of an active schema of spatially related reward loci. In another experiment, I extended these findings to explore a schema of object and place associations. Ensemble activity was influenced by a hierarchy of task dimensions which included: experimental context, rat's spatial location, the reward potential and the identity of sampled objects. As rats learned about new objects, the cells that had previously fired for particular object-place conjunctions generalized their firing patterns to new conjunctions that similarly predicted reward. In both experiments, I observed highly structured representations for a set of related experiences. This organization of hippocampal activity counters key assumptions in standard models of hippocampal function that predict relative independence between memory traces. Instead, these findings reveal neural mechanisms for how the hippocampus develops a relational organization of memories that could support novel, inferential judgments between indirectly related events

Computational analyses of the role of hippocampal oscillations in familiar and novel environments.

The hippocampal formation is known to support several different types of spatial representation, and to play an important role in detecting environmental novelty. A striking aspect of hippocampal physiology is the theta rhythm, recorded in the electroencephalogram (EEG). This thesis investigates the role of the theta rhythm as an organising principle of the hippocampal formation, and in particular its role in the detection of novelty. In the first experimental chapter, the behavioural correlates of principal cells across several regions of the hippocampal formation - head direction and conjunctive place by direction cells in the presubiculum, place cells in CA1 and grid cells in the MEC - are studied, with an emphasis on the contribution of running speed. Subpopulations of cells, both positively and a minority which are negatively modulated by speed are found in each region. The second experimental chapter investigates the predictions of a recent model of entorhinal cortical grid cells. The model, based on the interference between somatic and dendritic oscillators, predicts that intrinsic firing frequency should exceed EEG theta frequency by a greater amount for small grids than for large grids and by a greater amount during fast running compared to slow. These relationships are confirmed in electrophysiological recordings in freely-moving rats. The third experimental chapter reports the results of a detailed examination of the rodent EEG under conditions of novelty and familiarity. The oscillatory interference model predicts a reduction in the theta frequency in a novel environmental context. This is substantiated by the data and reveals a new mechanism for signalling novelty in the brain. The fourth experimental chapter probes the specific roles played by the subiculum and CA1. There is debate as to whether the subiculum is an input as well as, traditionally considered, an output of the HF. I propose that subiculum is capable of informing CA1 and data is presented to show that subicular firing occurs earlier in the theta cycle and anticipates position further ahead than firing in CA1 does, and that this difference is modulated by familiarity with the environment

Factors influencing functional recovery following hemidecortication in rats

x, 123 leaves ; 29 cm.Large neocortical lesions, such as hemidecortication, are detrimental for motor and cognitive skills. This thesis investigates the effect of age at the time of lesion on functional outcome. Attempts were then made to improve the outcome by using two simple treatments, tactile stimulation and Fibroblast Growth Factor-2 (FGF-2). The functional outcome of animals was measured using a series of behavioural tests (Morris water task, skilled reaching, forelimb placing during spontaneous vertical exploration, and the sunflower seed task). A qualitative difference was noted between animals that received hemidecortication at post natal day ten (P 10) versus animals that received a hemidecortication in adulthood (postnatal day, P 90). When the tactile stimulation treatment was used on animals that received P 10 hemidecortication, cognitive and motor improvements were noted. The same was not true for injections of FGF-2. When given after P 10 hemidecortication, this treatment impaired the cognitive abilities of rats in the Morris water task. There are two main points from this project: 1) overall functional recovery is not better or worse but simply different based on the age at which the trauma occurred and 2) treatments have varied success with different types of brain injury

Development of a Rat-like Robot and Its Applications in Animal Behavior Research

制度:新 ; 報告番号:甲3587号 ; 学位の種類:博士(工学) ; 授与年月日:2012/3/15 ; 早大学位記番号:新592

Pearce-Hall Attention for Learning Parameter: Memory Substrates

This thesis expands our characterization of brain circuits that implement attention to facilitate learning according to Pearce & Hall (1980) rules. In the Pearce & Hall (1980) model, the dynamic attention parameter (α) is the variable that determines the selection of cues to learn about. For every registered cue, the value of α is adjusted towards the amount of contemporaneous surprise (prediction error), and then stored in memory. Considerable work by Holland, Gallagher & associates revealed the existence of an amygdalo–nigral–cortical circuit that underlies the encoding and expression of α. In each of the 8 experiments in this thesis, rats were trained in a serial prediction task, and intraparenchymal microinfusions of transient action pharmacological agents were delivered at separable stages of α memory processing. The first three experiments establish posterior parietal cortex (PPC) as a candidate storage locus by demonstrating its importance during α encoding, consolidation, and expression. The next experiment dissociated the roles PPC and adjoining secondary visual cortex (V2) during encoding, and the subsequent experiment revealed V2 to be a novel component of the α expression module. The three final experiments suggested a role for amygdala central nucleus (CeA) in modulating α memory consolidation. Circuit implications are discussed throughout

Contributions of synaptic filters to models of synaptically stored memory

The question of how neural systems encode memories in one-shot without immediately disrupting previously stored information has puzzled theoretical neuroscientists for years and it is the central topic of this thesis. Previous attempts on this topic, have proposed that synapses probabilistically update in response to plasticity inducing stimuli to effectively delay the degradation of old memories in the face of ongoing memory storage. Indeed, experiments have shown that synapses do not immediately respond to plasticity inducing stimuli, since these must be presented many times before synaptic plasticity is expressed. Such a delay could be due to the stochastic nature of synaptic plasticity or perhaps because induction signals are integrated before overt strength changes occur.The later approach has been previously applied to control fluctuations in neural development by low-pass filtering induction signals before plasticity is expressed. In this thesis we consider memory dynamics in a mathematical model with synapses that integrate plasticity induction signals to a threshold before expressing plasticity. We report novel recall dynamics and considerable improvements in memory lifetimes against a prominent model of synaptically stored memory. With integrating synapses the memory trace initially rises before reaching a maximum and then falls. The memory signal dissociates into separate oblivescence and reminiscence components, with reminiscence initially dominating recall. Furthermore, we find that integrating synapses possess natural timescales that can be used to consider the transition to late-phase plasticity under spaced repetition patterns known to lead to optimal storage conditions. We find that threshold crossing statistics differentiate between massed and spaced memory repetition patterns. However, isolated integrative synapses obtain an insufficient statistical sample to detect the stimulation pattern within a few memory repetitions. We extend the modelto consider the cooperation of well-known intracellular signalling pathways in detecting storage conditions by utilizing the profile of postsynaptic depolarization. We find that neuron wide signalling and local synaptic signals can be combined to detect optimal storage conditions that lead to stable forms of plasticity in a synapse specific manner.These models can be further extended to consider heterosynaptic and neuromodulatory interactions for late-phase plasticity.<br/