The aim of this thesis is to examine the underlying cognitive and neural processes at play during retrieval of temporal and contextual source information. This was assessed across three experimental chapters. In the first experimental chapter, Chapter 2, the neural loci of context associations were assessed. Rats trained on an odour-context association task were given lesions to either the Lateral Entorhinal Cortex (LEC) or sham lesions. After surgery, performance on the odour-context task was assessed. It was hypothesised that memory for previously learned odour-context associations would be impaired following LEC lesions but not sham lesions. The results supported this hypothesis, demonstrating impaired memory for the previously learned odour-context associations in the LEC lesion group compared to the Sham lesion. In Chapter 3, the underlying retrieval processes used to retrieve time and context in human memory was assessed across three experiments. It was hypothesised that time would be remembered accurately using both recollection and familiarity, while correct context memory should rely on recollection alone. Two out of the three experiments supported this hypothesis, demonstrating that temporal information can be retrieved using familiarity in certain instances. The final experimental Chapter 4 used fMRI to extend Chapter 3 and examine whether neural activity would be greater in regions associated with recollection during memory for context, while activity in familiarity-related regions would be higher during memory for time. Results revealed no support for these predictions with no regions linked to recollection showing greater context-related activity, and no regions previously linked to familiarity exhibiting increased activation as temporal information was retrieved. The results are discussed in relation to established recollection and familiarity frameworks and previous work examining the neural substrates supporting memory for time and context.

OBJECTIVE: To determine whether volumetric measures of the hippocampus or entorhinal cortex in combination with other cortical measures can differentiate between cognitively normal individuals and participants with amnestic mild cognitive impairment (MCI). METHODS: T1-weighted magnetic resonance imaging (MRI) data acquired from 46 cognitively normal participants and 50 participants with amnestic MCI as part of the Boston University Alzheimer's Disease Center research registry and the Alzheimer's Disease Neuroimaging Initiative were used in this cross-sectional study. Cortical and subcortical volumes, including hippocampal subfield volumes, were automatically generated from each participant’s structural MRI data using FreeSurfer v6.0. Nominal logistic regression models containing these variables were used to evaluate their ability to identify participants with MCI. RESULTS: A model containing 11 regions of interest (insula, superior parietal cortex, rostral middle frontal cortex, middle temporal cortex, pars opercularis, paracentral lobule, whole hippocampus, subiculum, superior temporal cortex, precentral cortex and caudal anterior cingulate cortex) fit the data best (R2 = 0.7710, whole model test chi square = 102.4794, p < 0.0001). CONCLUSIONS: Volumetric measures acquired from MRI were able to correctly identify most healthy control subjects and those with amnestic MCI using measures of selected medial temporal lobe structures in combination with those from other cortical areas yielding an overall classification of 95.83% for this dataset. These findings support the notion that while clinical features of amnestic MCI may reflect medial temporal atrophy, differences that can be used to distinguish between these two populations are present elsewhere in the brain. This finding further affirming that atrophy can be identified before clinical features are expressed. Additional studies are needed to assess how well other imaging modalities, such as resting state functional connectivity, diffusion imaging, and amyloid and tau position emission tomography (PET), perform in classifying participants who are cognitively normal versus those who are amnestic MCI.

One of the few areas in the brain that still exhibits experience-dependent neuroplasticity in adulthood is found in the medial temporal lobe (MTL) system. Within the MTL, this plasticity has been observed in the hippocampus in both humans and animal models. Rodent model studies focusing on the effect of aerobic exercise have shown a positive increase of neuroplasticity in the dentate gyrus subregion of the hippocampus. Another area in the MTL, the entorhinal cortex (EC), serves as a primary input to the hippocampus, and studies on environmental enrichment have reported greater EC volume in rodents supplied with toys and running wheels. Previous work in our lab working with healthy young adults showed a positive correlation between right EC volume, and aerobic fitness (VO2 max). In this thesis, I examined two aims, first whether aerobic fitness predicts changes in thickness or volume of the MTL as well as performance in an MTL dependent task in healthy young adults. Additionally, whether the brain morphology measures of the MTL can predict performance on the memory task. The second aim looks at the longitudinal effect a 12-week exercise intervention has on thickness or volume in the MTL and performance on an MTL dependent task in the same population. Results indicate that there is a positive baseline correlation between aerobic fitness and thickness of the EC on the left hemisphere but there are no longitudinal changes in morphology after the exercise intervention. These data extend previous work on the effects aerobic exercise has on MTL structure and offer interesting venues to combat neurodegenerative diseases that affect the MTL memory system like Alzheimer’s disease.

Trimethyltin (TMT) is known to produce substantial damage to the hippocampal formation. It also destroys neurons within the entorhinal cortex, thereby causing degeneration of perforant path afferents that terminate in the outer molecular layer (OML) of the dentate gyrus. Surgical destruction of the entorhinal cortex also causes the perforant path to degenerate. This leads to reactive synpatogenesis (axonal sprouting) of septal afferents to the dentate gyrus. The purpose of the present study was to determine whether administration of 6 mg/kg of TMT by gavage to rats would cause axonal sprouting within the septodentate projection. A histochemical stain for acetycholinesterase (AChE) was used. Compared to control subjects rats given TMT exhibited significantly denser AChE staining in the dentate OML. This is putative indication of reactive synaptogenesis within the cholinergic projection to this layer of the dentate and is somewhat surprising because other neurotoxins, such as lead and ethanol, that affect neurons within the hippocampal formation reduce the capacity for reactive synaptogenesis in response to lesions of the entorhinal cortex.

The visual system is able to form relationships across a variety of timescales. These relationships could allow the temporal continuity of the retinal image and the underlying temporal structure of the world to serve as key cues in invariant object recognition (the ability of the visual system to recognize objects across a variety of angles, distances, and other conditions) as well as other visual processes at longer timescales. To utilize this temporal continuity and temporal structure the visual system needs a continuous temporal signal that spans multiple timescales and a computational mechanism for forming relationships across this temporal signal. Two studies (Chapters 2 and 3) showed evidence for a temporal signal that could be used in vision in the monkey brain. Time cells, neurons that fire at particular time intervals relative to a stimulus, could be a component of this temporal signal. Evidence of time cells was found through analysis of neural recording from monkey HPC and PFC during a memory task that requires the monkey to associate visual stimuli separated by about a second in time. After the first stimulus was presented, large numbers of units in both HPC and PFC fired in sequence. Many units fired only when a particular stimulus was presented at a particular time in the past. The temporal information of time cells might originate in another form of temporal coding: temporal context cells. Temporal context cells are neurons that quickly change in firing rate in response to a stimuli then slowly relax back to a baseline firing rate. Evidence of temporal context cells was found by analyzing the temporal responses of neural recordings from the entorhinal cortex of macaque monkeys as they viewed complex images. Many neurons in the entorhinal cortex were responsive to image onset, showing large deviations from baseline firing shortly after image onset but relaxing back to baseline at different rates. This range of relaxation rates allowed for the time since image onset to be decoded on the scale of seconds. Further, these neurons carried information about image content, suggesting that neurons in the entorhinal cortex carry information not only about when an event took place but also the identity of that event. Taken together, these findings suggest that the primate entorhinal cortex uses a spectrum of time constants to construct a temporal record of the past in support of episodic memory. A computational model was implemented that can construct and use this putative temporal record to form relationships across timescales. This model is supported by empirical results in visual experiments at timescales of saccades, seconds, and tens of seconds. At the saccadic timescale, this association across time could be relevant to forming invariant object representations.

Regulation of metabolism is vital to health and lies at the core of many different diseases. The breakdown of metabolisms' regulation within the brain can lead to neurological disease like Alzheimer's Disease (AD). AD is known to affect brain regions responsible for memory and memory processing like the hippocampus and entorhinal cortex. The regulation of these regions' protein quality, synthesis, and degradation deviate from 'normal' or 'healthy' levels when AD is happening. It is known there is a breakdown of regulation in those regions; however, little is known about the specifics of regulation in healthy brains regions or how it changes with disease. Using the sample collection method of microsampling in combination with kinetic proteomics we investigated proteostasis control in regions known to be affected by AD relative to a control region. This provides a baseline for proteins and ontologies found in the proteomes under healthy circumstances. The regions are all the same tissue type; however, since different regions of the brain perform different functions, the metabolism and therefore the regulation of proteostasis are different. By understanding how regional brain proteomes are regulated in young healthy mice, we are prepared for comparisons against diseased tissue in future work.

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Oscillatory states in the Electroencephalogram (EEG) reflect the rhythmic synchronous activation in large networks of neurons. Time-frequency methods quantify the spectral content of the EEG as a function of time. As such, they are well suited as tools for the study of spontaneous and induced changes in oscillatory states. We have used time-frequency techniques to analyze the flow of activity patterns between two strongly connected brain structures: the entorhinal cortex and the hippocampus, which are believed to be involved in information storage. EEG was recorded simultaneously from the entorhinal cortex and the hippocampus of behaving rats. During the recording, low-intensity trains of electrical pulses at frequencies between 1 and 40 Hz were applied to the olfactory (piriform) cortex. The piriform cortex projects to the entorhinal cortex, which then passes the signal on to the hippocampus. Several time-frequency methods, including the short-time Fourier transform (STFT), Wigner-Ville distribution (WVD) and multiple window (MW) time-frequency analysis (TFA), were used to analyse EEG signals. To monitor the signal transmission between the entorhinal cortex and hippocampus, the time-frequency coherence functions were used. The analysed results showed that stimulation-related power in both sites peaked near 15 Hz, but the coherence between the EEG signals recorded from these two sites increased monotonically with stimulation frequency. Among the time-frequency methods used, the STFT provided time-frequency distributions not only without cross-terms which were present in the WVD, but also with higher resolutions in both time and frequency than the MW-TFA. The STFT seems to be the most suitable time-frequency method to study the stimulation-induced signals presented in this thesis. The MW-TFA, which gives low bias and low variance estimations of the time-frequency distribution when only one realization of data is given, is suitable for stochastic and nonstationary signals such as spontaneous EEG. We also compared the performance of the MW-TFA using two different window functions: Slepian sequences and Hermite functions. By carefully matching the two window functions, we found no noticeable difference in time-frequency plane between them. / Thesis / Master of Engineering (ME)

Tauopathy, which results from the oligomerization of misfolded tau protein in neurons, is a feature present in a number of neurodegenerative diseases and a hallmark of Alzheimer’s Disease (AD). Tau is an important phosphoprotein that regulates the assembly of microtubules, but tauopathy can occur when tau becomes hyperphosphorylated. Phosphorylation prevents tau from binding to tubulin, which results in cytosolic accumulation of tau and eventual oligomerization. This abnormal accumulation of tau leads to the spreading of hyperphosphorylated tau to downstream synaptically connected neurons through an unknown mechanism. In AD, the hippocampus is one of the first brain structures to be affected by tauopathy in humans. According to previous research, tauopathy occurs primarily between principal cells in the hippocampus. The involvement of local inhibitory interneurons in tauopathy and their potential role in AD is more controversial. Previous research suggests that tau pathogenesis primarily affects principal cells; however, given the importance, diversity, and function of interneurons in the hippocampus, it is important to gain a better understanding of the interneuron subtypes that may be impacted by the spread of trans-synaptic tau into the hippocampus. Understanding the involvement of interneurons in trans-synaptic tau transmission is important to understanding neurodegeneration in AD and other neurodegenerative disorders. To investigate this, both male and female genetically-modified mice underwent surgery to examine the trans-synaptic spread of pathogenic tau (EGFP-Tau P301L) from the entorhinal cortex to hippocampal neurons. Histology and imaging analysis of brain sections were performed to examine the hippocampal cells impacted by trans-synaptic spread of tau. Results show that pathogenic tau can trans-synaptically spread from presynaptic neurons in the entorhinal cortex into downstream hippocampal interneurons and also that hippocampal interneurons are capable of trans-synaptically spreading tau. Future studies examining the specific subtypes of hippocampal interneurons vulnerable to trans-synaptic spread of tau will be important for a better understanding of disease progression, which could lead to uncovering new therapeutic targets for neurodegenerative diseases, like AD, which are associated with tauopathy.