Episodic memories are encoded by a sparse population of hippocampal neurons. In mice, optogenetic manipulation of this memory engram established that these neurons are indispensable and inducing for memory recall. However, little is known about their in vivo activity or precise role in memory. We found that during memory encoding, only a fraction of CA1 place cells function as engram neurons, distinguished by firing repetitive bursts paced at the theta frequency. During memory recall, these neurons remained highly context specific, yet demonstrated preferential remapping of their place fields. These data demonstrate a dissociation of precise spatial coding and contextual indexing by distinct hippocampal ensembles and suggest that the hippocampal engram serves as an index of memory content.
Abstract-Recent studies suggest that vascular risk factors play a considerable role in the development of Alzheimer disease. Furthermore, the use of antihypertensive drugs has been suggested to reduce the incidence of dementia, including Alzheimer disease. In this study, we examined the effects of an angiotensin receptor blocker, olmesartan, on -amyloid-induced cerebrovascular dysfunction and cognitive impairment. Oral administration of a low dose of olmesartan attenuated cerebrovascular dysfunction in young Alzheimer disease-model transgenic mice (APP23 mouse), without a reduction in the brain -amyloid level. Moreover, treatment of APP23 mice with olmesartan decreased oxidative stress in brain microvessels. Using an acute mouse model induced by ICV administration of -amyloid 1-40, we assessed the effect of oral administration of olmesartan on spatial learning evaluated with the Morris water maze.Olmesartan significantly improved cognitive function independent of its blood pressure-lowering effect, whereas there was no improvement by other types of antihypertensive drugs (hydralazine and nifedipine). We found that pretreatment with a low dose of olmesartan completely prevented -amyloid-induced vascular dysregulation and partially attenuated the impairment of hippocampal synaptic plasticity. These findings suggest the possibility that amelioration of cerebrovascular dysfunction with an angiotensin receptor blocker could be a novel therapeutic strategy for the early stage of Alzheimer disease. Key Words: angiotensin receptor blocker Ⅲ hypertension Ⅲ renin-angiotensin system Ⅲ dementia Ⅲ Alzheimer disease A lzheimer disease (AD) is the most common form of dementia. One of the major neuropathological hallmarks of AD is accumulation of -amyloid peptide (A) in the brain. 1 A is a 38-to 43-amino acid peptide produced from amyloid precursor protein (APP) by proteolytic processing. Abnormal accumulation of A-peptide in the brain is associated with a cascade of pathological events, resulting in dementia. 1 Recently, alterations in cerebrovascular regulation related to vascular oxidative stress have been implicated in the mechanisms of the early stage of AD. [2][3][4] The strategy for AD treatment is shifting to earlier stage intervention or prevention of this disease. Amelioration of cerebrovascular dysregulation could be a novel therapeutic target.Importantly, there is a growing body of evidence indicating an association between vascular risk factors and AD. 5 Several epidemiological studies have shown that hypertension in midlife is related to the development of AD. 5,6 Furthermore, some antihypertensive drugs reduce the incidence of dementia, including AD. For example, in the Systolic Hypertension in Europe Study, active therapy with a calcium channel blocker, nitrendipine, reduced the incidence of AD. 7 The Cache County Study of Memory and Aging concluded that the use of antihypertensive medication is associated with a lower incidence of AD. 8 On the other hand, previous studies have revealed contributory ...
Lateral habenula (LHb) has attracted growing interest as a regulator of serotonergic and dopaminergic neurons in the CNS. However, it remains unclear how the LHb modulates brain states in animals. To identify the neural substrates that are under the influence of LHb regulation, we examined the effects of rat LHb lesions on the hippocampal oscillatory activity associated with the transition of brain states. Our results showed that the LHb lesion shortened the theta activity duration both in anesthetized and sleeping rats. Furthermore, this inhibitory effect of LHb lesion on theta maintenance depended upon an intact serotonergic median raphe, suggesting that LHb activity plays an essential role in maintaining hippocampal theta oscillation via the serotonergic raphe. Multiunit recording of sleeping rats further revealed that firing of LHb neurons showed significant phase-locking activity at each theta oscillation cycle in the hippocampus. LHb neurons showing activity that was coordinated with that of the hippocampal theta were localized in the medial LHb division, which receives afferents from the diagonal band of Broca (DBB), a pacemaker region for the hippocampal theta oscillation. Thus, our findings indicate that the DBB may pace not only the hippocampus, but also the LHb, during rapid eye movement sleep. Since serotonin is known to negatively regulate theta oscillation in the hippocampus, phase-locking activity of the LHb neurons may act, under the influence of the DBB, to maintain the hippocampal theta oscillation by modulating the activity of serotonergic neurons.
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