Lesion of the hippocampus selectively enhances LEC’s activity during recognition memory based on familiarity

The sense of familiarity for events is crucial for successful recognition memory. However, the neural substrate and mechanisms supporting familiarity remain unclear. A major controversy in memory research is whether the parahippocampal areas, especially the lateral entorhinal (LEC) and the perirhinal (PER) cortices, support familiarity or whether the hippocampus (HIP) does. In addition, it is unclear if LEC, PER and HIP interact within this frame. Here, we especially investigate if LEC and PER's contribution to familiarity depends on hippocampal integrity. To do so, we compare LEC and PER neural activity between rats with intact hippocampus performing on a human to rat translational task relying on both recollection and familiarity and rats with hippocampal lesions that have been shown to then rely on familiarity to perform the same task. Using high resolution Immediate Early Gene imaging, we report that hippocampal lesions enhance activity in LEC during familiarity judgments but not PER’s. These findings suggest that different mechanisms support familiarity in LEC and PER and led to the hypothesis that HIP might exert a tonic inhibition on LEC during recognition memory that is released when HIP is compromised, possibly constituting a compensatory mechanism in aging and amnesic patients.

Anterior thalamic nuclei: A critical substrate for non-spatial paired-associate memory

The anterior thalamic nuclei (ATN), a central node in a complex memory system, process spatial and temporal memory. Here, we show that ATN lesions do not affect acquisition of a simple odour discrimination or a simple object discrimination in a runway apparatus. The same procedures were used to test learning of an arbitrary association between non-spatial object-odour pairings (A+X or B+Y were rewarded; but not A+Y or B+X). If ATN lesions recapitulate hippocampal function, specifically CA1 function, then they should disrupt acquisition only when an explicit delay (i.e., a 10-second trace) is inserted between the odour and object. Acquisition was completely abolished by ATN lesions, irrespective of the presence of the temporal trace, and despite extensive training (50x12-trial sessions). Faster acquisition with the 10-second trace was found in the sham-lesion rats. During recall, 5 days after criterion, sham rats but not ATN-lesion rats showed elevated Zif268 expression in hippocampal CA1 for the trace compared to no-trace condition; both sham and lesion rats tested in the trace condition showed increased IEG expression in the superficial layers of the prefrontal cortex and retrosplenial cortex. ATN lesions markedly reduced Zif268 expression in the prefrontal cortex and retrosplenial cortex. This is the first evidence that ATN lesions impair non-spatial paired-associate tasks. The findings suggest that the ATN influence memory beyond time and space, and constitute a critical neural structure for learning arbitrary associations even in the task version that is not disrupted by hippocampal lesions.

Life and Death of Immature Neurons in the Juvenile and Adult Primate Amygdala

In recent years, a large population of immature neurons has been documented in the paralaminar nucleus of the primate amygdala. A substantial fraction of these immature neurons differentiate into mature neurons during postnatal development or following selective lesion of the hippocampus. Notwithstanding a growing number of studies on the origin and fate of these immature neurons, fundamental questions about the life and death of these neurons remain. Here, we briefly summarize what is currently known about the immature neurons present in the primate ventral amygdala during development and in adulthood, as well as following selective hippocampal lesions. We provide evidence confirming that the distribution of immature neurons extends to the anterior portions of the entorhinal cortex and layer II of the perirhinal cortex. We also provide novel arguments derived from stereological estimates of the number of mature and immature neurons, which support the view that the migration of immature neurons from the lateral ventricle accompanies neuronal maturation in the primate amygdala at all ages. Finally, we propose and discuss the hypothesis that increased migration and maturation of neurons in the amygdala following hippocampal dysfunction may be linked to behavioral alterations associated with certain neurodevelopmental disorders.

Lesion of The Hippocampus Selectively Enhances LEC's Activity During Recognition Memory Based On Familiarity

The sense of familiarity for events is crucial for successful recognition memory. However, the neural substrate and mechanisms supporting familiarity remain unclear. A major controversy in memory research is whether the parahippocampal areas, especially the lateral entorhinal (LEC) and the perirhinal (PER) cortices, support familiarity or whether the hippocampus (HIP) does. In addition, it is unclear if LEC, PER and HIP interact within this frame. Here, we especially investigate if LEC and PER's contribution to familiarity depends on hippocampal integrity. To do so, we compare LEC and PER neural activity between rats with intact hippocampus performing on a human to rat translational task relying on both recollection and familiarity and rats with hippocampal lesions that have been shown to then rely on familiarity to perform the same task. Using high resolution Immediate Early Gene imaging, we report that hippocampal lesions enhance activity in LEC during familiarity judgments but not PER’s. These findings suggest that different mechanisms support familiarity in LEC and PER and led to the hypothesis that HIP might exert a tonic inhibition on LEC during recognition memory that is released when HIP is compromised, possibly constituting a compensatory mechanism in aging and amnesic patients.

FMRI Investigation of Spatial Memory Abilities in Individuals Living With Schizophrenia Spectrum Disorders

Different strategies dependent on different brain regions may be spontaneously adopted to solve most spatial memory and navigation tasks. For this dissertation, I used brain-imaging and cognitive tasks to test the hypothesis that individuals living with schizophrenia spectrum disorders (SSD) have selective hippocampal-dependent spatial memory impairment. A hippocampal-dependent spatial strategy (locale/allocentric/cognitive map/viewpoint-independent) involves relying on learning the relations between landmarks in the environment, whereas a response strategy (taxon/egocentric/viewpoint-dependent) is more associated with caudate function and involves learning a sequence from a single starting position. In Experiment 1, I examined performance and brain activation with fMRI during the 4-on-8 virtual maze (4/8VM) to test the hypothesis of intact response versus impaired spatial memory in SSD. The SSD participants who adopted a spatial strategy performed more poorly and had less hippocampal activation than other groups. In Experiment 2, I further examined these data using multivariate PLS (partial least squares) analyses to identify whole-brain patterns of activation associated with group and strategy differences on the 4/8VM. Results revealed clusters of correlated activation within the temporal lobe unique to the SSD-Spatial group. The SSD Response group activated the same regions as the Healthy groups, but to a greater extent suggesting over-activation. In contrast to the between-subjects nature of strategy differences on the 4/8VM, for Experiment 3 I used the Courtyard Task to seek converging evidence of a selective hippocampal-dependent impairment in spatial memory using a within-subjects design. The Courtyard Task has previously demonstrated impaired performance among individuals with hippocampal lesions under shifted-view (allocentric) but not same-view (egocentric) conditions. Consistent with a profile of hippocampal dysfunction, the SSD group demonstrated a particular deficit under the shifted-view condition. The results support the development of protocols to train impaired hippocampal-dependent abilities and harness non-hippocampal dependent intact abilities. Overall, this dissertation provides valuable information characterizing spatial memory and highlights the importance of strategy use in SSD.

FMRI Investigation of Spatial Memory Abilities in Individuals Living With Schizophrenia Spectrum Disorders

Different strategies dependent on different brain regions may be spontaneously adopted to solve most spatial memory and navigation tasks. For this dissertation, I used brain-imaging and cognitive tasks to test the hypothesis that individuals living with schizophrenia spectrum disorders (SSD) have selective hippocampal-dependent spatial memory impairment. A hippocampal-dependent spatial strategy (locale/allocentric/cognitive map/viewpoint-independent) involves relying on learning the relations between landmarks in the environment, whereas a response strategy (taxon/egocentric/viewpoint-dependent) is more associated with caudate function and involves learning a sequence from a single starting position. In Experiment 1, I examined performance and brain activation with fMRI during the 4-on-8 virtual maze (4/8VM) to test the hypothesis of intact response versus impaired spatial memory in SSD. The SSD participants who adopted a spatial strategy performed more poorly and had less hippocampal activation than other groups. In Experiment 2, I further examined these data using multivariate PLS (partial least squares) analyses to identify whole-brain patterns of activation associated with group and strategy differences on the 4/8VM. Results revealed clusters of correlated activation within the temporal lobe unique to the SSD-Spatial group. The SSD Response group activated the same regions as the Healthy groups, but to a greater extent suggesting over-activation. In contrast to the between-subjects nature of strategy differences on the 4/8VM, for Experiment 3 I used the Courtyard Task to seek converging evidence of a selective hippocampal-dependent impairment in spatial memory using a within-subjects design. The Courtyard Task has previously demonstrated impaired performance among individuals with hippocampal lesions under shifted-view (allocentric) but not same-view (egocentric) conditions. Consistent with a profile of hippocampal dysfunction, the SSD group demonstrated a particular deficit under the shifted-view condition. The results support the development of protocols to train impaired hippocampal-dependent abilities and harness non-hippocampal dependent intact abilities. Overall, this dissertation provides valuable information characterizing spatial memory and highlights the importance of strategy use in SSD.

The spatiotemporal organization of experience dictates hippocampal involvement in primary visual cortical plasticity

The hippocampus and neocortex are theorized to be crucial partners in the formation of long-term memories. Here, we assess hippocampal involvement in two related forms of experience-dependent plasticity in the primary visual cortex (V1) of mice. Like control animals, those with hippocampal lesions exhibit potentiation of visually evoked potentials following passive daily exposure to a phase reversing oriented grating stimulus, which is accompanied by long-term habituation of a reflexive behavioral response. Thus, low-level recognition memory is formed independently of the hippocampus. However, response potentiation resulting from daily exposure to a fixed sequence of four oriented gratings is severely impaired in mice with hippocampal damage. A feature of sequence plasticity in V1 of controls, but absent in lesioned mice, is generation of predictive responses to an anticipated stimulus element when it is withheld or delayed. Thus, hippocampus is involved in encoding temporally structured experience, even in primary sensory cortex.