Hippocampus最新文献

The entorhinal cortex sends afferent information to the hippocampus by means of the perforant path (PP). The PP input to the dentate gyrus (DG) terminates in the suprapyramidal (sDG) and infrapyramidal (iDG) blades. Different electrophysiological stimulation patterns of the PP can generate hippocampal synaptic plasticity. Whether frequency-dependent synaptic plasticity differs in the sDG and iDG is unclear. Here, we compared medial PP–DG responses in freely behaving adult rats and found that synaptic plasticity in the sDG is broadly frequency dependent, whereby long-term depression (LTD, > 24 h) is induced with stimulation at 1 Hz, short-term depression (< 2 h) is triggered by 5 or 10 Hz, and long-term potentiation (LTP) of increasing magnitudes is induced by 200 and 400 Hz stimulation, respectively. By contrast, although the iDG expresses STD following 5 or 10 Hz stimulation, LTD induced by 1 Hz is weaker, LTP is not induced by 200 Hz and LTP induced by 400 Hz stimulation is significantly smaller in magnitude than LTP induced in sDG. Furthermore, the stimulus–response relationship of iDG is suppressed compared to sDG. These differences may arise from differences in granule cell properties, or the complement of NMDA receptors. Patch clamp recordings, in vitro, revealed reduced firing frequencies in response to high currents, and different action potential thresholds in iDG compared to sDG. Assessment of the expression of GluN subunits revealed significantly lower expression levels of GluN1, GluN2A, and GluN2B in the middle molecular layer of iDG compared to sDG. Taken together, these data indicate that synaptic plasticity in the iDG is weaker, less persistent and less responsive to afferent frequencies than synaptic plasticity in sDG. Effects may be mediated by weaker NMDA receptor expression and differences in neuronal responses in iDG versus sDG. These characteristics may explain reported differences in experience-dependent information processing in the suprapyramidal and infrapyramidal blades of the DG.

The hippocampus plays a crucial role in acquiring, storing, and retrieving associative experience. Whereas neuromodulatory control of the hippocampus by the locus coeruleus (LC) enhances memory acquisition and consolidation, less is known about its influence on memory retrieval. The LC fires at tonic (0.5–8 Hz) and phasic frequencies (10–25 Hz), relative to arousal and affective states. Here, we explored to what extent LC stimulation at different frequencies (2–100 Hz) and respective stimulation patterns, before retrieval of recently acquired or remote spatial memory, alter working memory (WM) or reference memory (RM) in male rats. Here, animals learned a spatial memory task in an eight-arm radial maze over a period of 15 days. LC stimulation before recent memory testing did not affect WM. However, LC stimulation at 20 or 100 Hz, but not 5–10 Hz, impaired retrieval of recently consolidated RM. These frequency-dependent impairments were abolished by intracerebral β-adrenergic receptor (β-AR), but not D1/D5 receptor, antagonism. When memory retrieval was assessed 4 weeks after initial consolidation (Day 34), RM was significantly impaired compared to the final day of recent memory testing (on Day 6). RM was not altered by LC stimulation before remote memory retrieval. However, LC stimulation at 2–100 Hz improved WM. Taken together, these data suggest that frequency-dependent NA release from the LC disrupts retrieval of recently acquired RM via activation of β-AR. Strikingly, increasing LC activity in general improves WM of a remotely acquired spatial learning task, assessed 4 weeks after the recent memory testing, suggesting that the increased effort of sustaining WM of a task learned in the past requires higher LC engagement.

Adolescent intermittent ethanol (AIE) exposure leads to persisting increases in glial markers and significantly decreases the neurogenic niche in the dentate gyrus of the hippocampus. Our previous study indicated that donepezil (DZ), a cholinesterase inhibitor, can reverse the AIE effect of decreased doublecortin (DCX), a neurogenic marker, and increased cleaved caspase 3, a marker of apoptosis, in the dentate gyrus of male rats. However, to date, no studies have assessed the effects of DZ on AIE effects in females. The purpose of this study was to determine whether DZ can reverse neuroimmune, neurogenic, and neuronal death effects in adulthood after AIE in female rats. Adolescent female rats were given 14 doses of ethanol (5 g/kg) over 24 days by intragastric gavage. Seventeen days later, DZ (2.5 mg/kg, 1.88 mL/kg, i.g., in water) was then administered daily for 4 days prior to sacrifice. Immunohistochemical techniques were utilized to determine the effects of DZ on AIE-induced changes in neurogenesis, cell death, glial, and neuroimmune markers. As expected, AIE decreased the neurogenic markers DCX, SOX2, and Ki-67 in the dentate gyrus and also caused an increase in the glial markers GFAP and Iba-1 in the hippocampus. The effects of AIE on neurogenic and glial markers were reversed by DZ treatment, but the reversal of AIE effects on glial markers was regionally specific within the hippocampus. Overall, these findings indicate that systemic DZ in adult female rats ameliorates the effects of AIE on neurogenesis, neuronal cell death, neuroimmune markers, and glial activation markers. Future studies will determine if DZ alters hippocampally driven behaviors, as well as the mechanisms underlying donepezil's effects.

During the 1990s and early 2000s, research in humans and in the nonhuman primate model of human amnesia revealed that tasks involving free viewing of images provided an exceptionally sensitive measure of recognition memory. Performance on these tasks was sensitive to damage restricted to the hippocampus as well as to damage that included medial temporal lobe cortices. Early work in my laboratory used free-viewing tasks to assess the neurophysiological correlates of recognition memory, and the use of naturalistic visual exploration opened rich avenues to assess other aspects of the impact of eye movements on neural activity in the hippocampus and entorhinal cortex. Here, I summarize two main lines of this work and some of the stories of the trainees who made essential contributions to these discoveries.