Do spatial and recognition memories have a lateralized processing by the dorsal hippocampus CA3?

Partial or Complete Loss of Norepinephrine Differentially Alters Contextual Fear and Catecholamine Release Dynamics in Hippocampal CA1

Sensory cortical ensembles exhibit differential coupling to ripples in distinct hippocampal subregions

Place cells in the hippocampus can maintain multiple representations of a single environment and respond to physical and/or trajectory changes by remapping. Within the hippocampus there are anatomical, electrophysiological, and behavioral dissociations between the dorsal and ventral hippocampus and within dorsal CA1. Arc expression was used to measure the recruitment of ensembles across different hippocampal subregions in rats trained to utilize two different cognitive strategies while traversing an identical trajectory. This behavioral paradigm allowed for the measurement of remapping in the absence of changes in external cues, trajectory traversed (future/past), running speed, motivation, or different stages of learning. Changes in task demands induced remapping in only some hippocampal regions: reorganization of cell ensembles was observed in dorsal CA1 but not in dorsal CA3. Moreover, a gradient was found in the degree of remapping within dorsal CA1 that corresponds to entorhinal connectivity to this region. Remapping was not seen in the ventral hippocampus: neither ventral CA1 nor CA3 exhibited ensemble changes with different cognitive demands. This contrasts with findings of remapping in both the dorsal and ventral dentate gyrus using this task. The results suggest that the dorsal pole of the hippocampus is more sensitive to changes in task demands.

On the participation of hippocampal PKC in acquisition, consolidation and reconsolidation of spatial memory

Intraneuronal accumulation of amyloid β (iAβ) has been linked to mild cognitive impairment that may precede Alzheimer's disease (AD) onset. This neuropathological trait was recently mimicked in a novel animal model of AD, the hemizygous transgenic McGill-R-Thy1-APP (Tg+/−) rat. The characterization of the behavioral phenotypes in this animal model could provide a baseline of efficacy for earlier therapeutic interventions. The aim of the present study was to undertake a longitudinal study of Aβ accumulation and a comprehensive behavioral evaluation of this transgenic rat model. We assessed exploratory activity, anxiety-related behaviors, recognition memory, working memory, spatial learning and reference memory at 3, 6, and 12 months of age. In parallel, we measured Aβ by ELISA, Western blots and semiquantitative immunohistochemistry in hippocampal samples. SDS-soluble Aβ peptide accumulated at low levels (~9 pg/mg) without differences among ages. However, Western blots showed SDS-resistant Aβ oligomers (~30 kDa) at 6 and 12 months, but not at 3 months. When compared to wild-type (WT), male Tg+/− rats exhibited a spatial reference memory deficit in the Morris Water Maze (MWM) as early as 3 months of age, which persisted at 6 and 12 months. In addition, Tg+/− rats displayed a working memory impairment in the Y-maze and higher anxiety levels in the Open Field (OF) at 6 and 12 months of age, but not at 3 months. Exploratory activity in the OF was similar to that of WT at all-time points. Spatial learning in the MWM and the recognition memory, as assessed by the Novel Object Recognition Test, were unimpaired at any time point. The data from the present study demonstrate that the hemizygous transgenic McGill-R-Thy1-APP rat has a wide array of behavioral and cognitive impairments from young adulthood to middle-age. The low Aβ burden and early emotional and cognitive deficits in this transgenic rat model supports its potential use for drug discovery purposes in early AD.

Different encoding of reward location in dorsal and intermediate hippocampus

Adverse life events occurring in early development can result in long-term effects on behavioural, physiological and cognitive processes. In particular, perinatal stressors impair neurogenesis in the hippocampus which consequently impairs memory formation. Exercise has previously been shown to have antidepressant effects and to increase cognitive functioning by increasing neurogenesis and neurotrophins in the hippocampus. The current study examined the effects of maternal separation, which has been shown to model anxiety in animals, and the effects of exercise on learning and memory. Forty-five male Sprague-Dawley rats were divided into four groups, maternally separated / non-runners, maternally separated / runners, non-separated / runners and non-separated / non-runners. Maternal separation occurred from postnatal day 2 (P2) to 14 (P14) for 3 h per day. Exercised rats were given voluntary access to individual running wheels attached to their cages from P29 to P49. Behavioural testing (Morris water maze (MWM) and object recognition tests) took place from P49 to P63. Maternally separated rats showed no significant difference in anxiety levels in the elevated plus maze and the open field compared to the normally reared controls. However, rats that were allowed voluntary access to running wheels showed increased levels of anxiety in the elevated plus maze and in the open field. Maternal separation did not have any effect on memory performance in the MWM or the object recognition tasks. Exercise increased spatial learning and memory in the MWM with the exercised rats displaying a decreased latency in locating the hidden platform than the non-exercised rats. The exercised rats spent significantly less time exploring the most recently encountered object in the temporal order task in comparison to the non-exercised controls, therefore showing improved temporal recognition memory. All groups performed the same on the other recognition tasks, with all rats showing intact memory performance. Results indicate that maternal separation had little effect on the rats whereas exercise enhanced both spatial and recognition memory.

Spatial navigation and orientation are emerging as promising markers for altered cognition in prodromal Alzheimer’s disease, and even in cognitively normal individuals at risk for Alzheimer’s disease. The different APOE gene alleles confer various degrees of risk. The APOE2 allele is considered protective, APOE3 is seen as control, while APOE4 carriage is the major known genetic risk for Alzheimer’s disease. We have used mouse models carrying the three humanized APOE alleles and tested them in a spatial memory task in the Morris water maze. We introduce a new metric, the absolute winding number, to characterize the spatial search strategy, through the shape of the swim path. We show that this metric is robust to noise, and works for small group samples. Moreover, the absolute winding number better differentiated APOE3 carriers, through their straighter swim paths relative to both APOE2 and APOE4 genotypes. Finally, this novel metric supported increased vulnerability in APOE4 females. We hypothesized differences in spatial memory and navigation strategies are linked to differences in brain networks, and showed that different genotypes have different reliance on the hippocampal and caudate putamen circuits, pointing to a role for white matter connections. Moreover, differences were most pronounced in females. This departure from a hippocampal centric to a brain network approach may open avenues for identifying regions linked to increased risk for Alzheimer’s disease, before overt disease manifestation. Further exploration of novel biomarkers based on spatial navigation strategies may enlarge the windows of opportunity for interventions. The proposed framework will be significant in dissecting vulnerable circuits associated with cognitive changes in prodromal Alzheimer’s disease.

Disclosure: S. Sims: None. F. Sen: None. F. Sultana: None. A. Liu: None. V. Laurencin: None. A. Gumerova: None. O. Barak: None. S. Rojekar: None. A.R. Pallapati: None. L. Cullen: None. R. Chen: None. K. Goosens: None. V. Ryu: None. T. Yuen: None. M. Zaidi: None. T. Frolinger: None. F. Korkmaz: None. Alzheimer’s disease (AD) is a major progressive neurodegenerative disorder of the aging population, accounting for more than 60-80% of dementia cases. High serum level of the pituitary gonadotropin, follicle-stimulating hormone (FSH), is strongly associated with the onset of AD. We recently showed that FSH activates hippocampal Fshr to drive AD–like pathology and cognitive impairment in AD mice, that FSH blockade in these mice abrogates the AD-like phenotype by inhibiting the neuronal C/EBPβ–δ-secretase pathway, and that FSH and ApoE4, the most prevalent genetic risk factor of AD, jointly trigger AD-like pathogenesis by activating C/EBPβ-δ-secretase signaling. To further confirm the role of FSH in AD cognitive decline, we used female 3xTg;Fshr+/+, 3xTg;Fshr+/– and 3xTg;Fshr–/– mice that underwent sham surgery or ovariectomy (OVX) at 8 weeks of age. Sham-operated 3xTg;Fshr–/– mice were implanted with 17β-estradiol pellets to normalize E2 levels. Morris Water Maze (MWM) and Novel object recognition (NOR) tests were perform in these mice to assess spatial and recognition memory, respectively. 3xTg;Fshr+/+ mice displayed impaired spatial memory at 5-month of age in the MWM test. This impairment, in both the learning and retrieval phases, is significantly ameliorated in 3xTg;Fshr–/– mice and to a lesser extent in 3xTg;Fshr+/– mice, suggesting that Fshr expression has a negative impact on memory. At 5 and 10 months of age, sham-operated 3xTg;Fshr–/– mice show better memory performance in the MWM test during the learning phase when compared to their wild-type littermates, suggesting a rescue of spatial memory and progression with age. However, this rescue was not seen when mice were ovariectomized. At 5 months of age, sham-operated 3xTg;Fshr–/– mice displayed better memory retrieval compared with 3xTg;Fshr+/+ mice. This effect was not observed when the mice were 10-month-old, suggesting that the beneficial effect of the absence of FSH signaling on memory consolidation could be masked by disease severity and older age. OVX 3xTg;Fshr+/+, 3xTg;Fshr+/– mice displayed a decline in memory consolidation at 10-months of age compared with 5-month of age, while the 3xTg;Fshr–/– mice showed a significantly slower decline. Using the NOR test, we found impaired recognition memory in 10-month-old sham-operated or OVX 3xTg;Fshr+/+ and 3xTg;Fshr+/– mice; this effect was prevented in OVX 3xTg;Fshr–/– mice. Finally, 3xTg;Fshr–/– mice displayed lower Aβ40 and Aβ42 levels in the brain (ELISA). Altogether, our results confirm a protective effect of absent Fshr signaling on spatial learning, consolidation, memory retrieval, recognition memory and reduction of brain Aβ40 and Aβ42. Presentation: 6/1/2024

The effects of orlistat on oxidative stress, recognition memory, spatial memory and hippocampal tissue in experimentally induced obesity in rats

Training with long inter-session intervals, termed distributed training, has long been known to be superior to training with short intervals, termed massed training. In the present study we compared c-Fos expression after massed and distributed training protocols in the Morris water maze to outline possible differences in the learning-induced pattern of neural activation in the dorsal CA1 in the two training conditions. The results demonstrate that training and time lags between learning opportunities had an impact on the pattern of neuronal activity in the dorsal CA1. Mice trained with the distributed protocol showed sustained neuronal activity in the postero-distal component of the dorsal CA1. In parallel, in trained mice we found more active cells that tended to constitute spatially restricted clusters, whose degree increased with the increase in the time lags between learning trials. Moreover, activated cell assemblies demonstrated increased stability in their spatial organization after distributed as compared to massed training or control condition. Finally, using a machine learning algorithm we found that differences in the number of c-Fos positive cells and their location in the dorsal CA1 could be predictive of the training protocol used. These results suggest that the topographic organization and the spatial location of learning activated cell assemblies might be critical to promote the increased stability of the memory trace induced by distributed training.

Reciprocal anatomical connections between hippocampus and subiculum in the rabbit: Evidence for subicular innervation of regio superior

Temporal association learning (TAL) allows for the linkage of distinct, nonsynchronous events across a period of time. This function is driven by neural interactions in the entorhinal cortical–hippocampal network, especially the neural input from the pyramidal cells in layer III of medial entorhinal cortex (MECIII) to hippocampal CA1 is crucial for TAL. Successful TAL depends on the strength of event stimuli and the duration of the temporal gap between events. Whereas it has been demonstrated that the neural input from pyramidal cells in layer II of MEC, referred to as Island cells, to inhibitory neurons in dorsal hippocampal CA1 controls TAL when the strength of event stimuli is weak, it remains unknown whether Island cells regulate TAL with long trace periods as well. To understand the role of Island cells in regulating the duration of the learnable trace period in TAL, we used Pavlovian trace fear conditioning (TFC) with a 60-sec long trace period (long trace fear conditioning [L-TFC]) coupled with optogenetic and chemogenetic neural activity manipulations as well as cell type-specific neural ablation. We found that ablation of Island cells in MECII partially increases L-TFC performance. Chemogenetic manipulation of Island cells causes differential effectiveness in Island cell activity and leads to a circuit imbalance that disrupts L-TFC. However, optogenetic terminal inhibition of Island cell input to dorsal hippocampal CA1 during the temporal association period allows for long trace intervals to be learned in TFC. These results demonstrate that Island cells have a critical role in regulating the duration of time bridgeable between associated events in TAL.

In the present study, we examined whether the effects induced by the bite-raised condition on glucocorticoid receptor (GR) expression differ between the dorsal and ventral hippocampus in SAMP8 mice. In the bite-raised condition, the number of GR-immunoreactive cells was significantly decreased in both the dorsal and ventral CA1 and dentate gyrus (DG) subfields of the hippocampus compared to control mice, as revealed by immunohistochemical analysis. The decrease in the number of GR-immunoreactive cells tended to be greater in the dorsal hippocampus than in the ventral hippocampus. Only in the DG subfield was there a significant difference in the number of GR-immunoreactive cells between the dorsal and ventral hippocampus. These findings suggest that in aged SAMP8 mice, the bite-raised condition decreases the number of GR-immunoreactive cells in both the dorsal and ventral hippocampus.

Muscarinic Modulation of Synaptic Transmission and Short-Term Plasticity in the Dorsal and Ventral Hippocampus