Focal Lesions of Human Hippocampal CA1 Neurons in Transient Global Amnesia Impair Place Memory

176

Vitamin D is an important calcium-regulating hormone with diverse functions in numerous tissues, including the brain. Increasing evidence suggests that vitamin D may play a role in maintaining cognitive function and that vitamin D deficiency may accelerate agerelated cognitive decline. Using aging rodents, we attempted to model the range of human serum vitamin D levels, from deficient to sufficient, to test whether vitamin D could preserve or improve cognitive function with aging. For 5-6 mo, middle-aged F344 rats were fed diets containing low, medium (typical amount), or high (100, 1,000, or 10,000 international units/kg diet, respectively) vitamin D3, and hippocampal-dependent learning and memory were then tested in the Morris water maze. Rats on high vitamin D achieved the highest blood levels (in the sufficient range) and significantly outperformed low and medium groups on maze reversal, a particularly challenging task that detects more subtle changes in memory. In addition to calcium-related processes, hippocampal gene expression microarrays identified pathways pertaining to synaptic transmission, cell communication, and G protein function as being up-regulated with high vitamin D. Basal synaptic transmission also was enhanced, corroborating observed effects on gene expression and learning and memory. Our studies demonstrate a causal relationship between vitamin D status and cognitive function, and they suggest that vitamin D-mediated changes in hippocampal gene expression may improve the likelihood of successful brain aging.V itamin D, a secosteroid hormone known for its role in bone and calcium homeostasis, is now well recognized for its many diverse functions and actions on a variety of tissues and cell types (1, 2). Vitamin D typically refers to the precursor forms of the hormone obtained through the skin's exposure to sunlight [vitamin D3 (VitD3)] or from dietary sources (VitD3 or VitD2). A metabolite of vitamin D, 25-hydroxyvitamin D (25OHD), is a serum biomarker of vitamin D status or repletion. In recent years, there is particular concern that large segments of the population may have low levels of 25OHD, and therefore are vitamin D-deficient (3). Due to factors such as reduced intake, absorption, and decreased exposure to sunlight, aging adults (≥50 y of age) are especially susceptible (3-6). Notably, this predisposition for lower 25OHD levels in the elderly has been linked to higher risk for numerous age-related disorders, including cancer and metabolic and vascular diseases (7-10).Inadequate vitamin D status also correlates with a greater risk for cognitive decline in the elderly (4,(11)(12)(13)(14)(15), suggesting that optimal levels may promote healthy brain aging (16,17). Because the brain expresses vitamin D receptors (VDRs) and can synthesize the active form of the hormone, the possible cognitive enhancing effects of vitamin D may reflect a primary action in the brain rather than a result of secondary systemic effects (18)(19)(20)(21)(22). Indeed, we and others have shown that vitamin D, as ...

Section: Discussionmentioning

confidence: 99%

“…The MWM task is used to test spatial reference memory and is widely thought to have relevance for human hippocampal-dependent memory (46)(47)(48)(49)(50). Although not as commonly used, reversal learning in the MWM is more difficult than the standard task, and therefore can be used to detect subtle memory deficits (46).…”

Section: Discussionmentioning

confidence: 99%

Vitamin D prevents cognitive decline and enhances hippocampal synaptic function in aging rats

Latimer¹,

Brewer²,

Searcy³

et al. 2014

176

“…The transient global amnesia (TGA) is a unique amnestic syndrome that is characterized by a rapid onset of an antero-and retrograde amnesia (11). A TGA usually lasts 6 to 10 h but is formally limited up to 24 h. In TGA patients, highly focal lesions confined to the CA1 field of the hippocampal cornu ammonis can be detected in high-resolution MRI 24 to 72 h after the amnestic phase (12,13).…”

mentioning

confidence: 99%

“…A TGA usually lasts 6 to 10 h but is formally limited up to 24 h. In TGA patients, highly focal lesions confined to the CA1 field of the hippocampal cornu ammonis can be detected in high-resolution MRI 24 to 72 h after the amnestic phase (12,13). These MRI lesions can be considered the structural correlate of the amnestic deficit reflecting a transient diaschisis of CA1-dependent circuits in terms of functional disconnection of the hippocampus (11,12,14). Here, we studied the effect of selective, acute, and focal lesions of hippocampal CA1 neurons on episodic autobiographical memory and autonoetic consciousness in patients with an acute TGA.…”

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confidence: 99%

CA1 neurons in the human hippocampus are critical for autobiographical memory, mental time travel, and autonoetic consciousness

Bartsch¹,

Döhring²,

Rohr

et al. 2011

226

148

Autobiographical memories in our lives are critically dependent on temporal lobe structures. However, the contribution of CA1 neurons in the human hippocampus to the retrieval of episodic autobiographical memory remains elusive. In patients with a rare acute transient global amnesia, highly focal lesions confined to the CA1 field of the hippocampus can be detected on MRI. We studied the effect of these lesions on autobiographical memory using a detailed autobiographical interview including the remember/know procedure. In 14 of 16 patients, focal lesions in the CA1 sector of the hippocampal cornu ammonis were detected. Autobiographical memory was significantly affected over all time periods, including memory for remote periods. Impairment of episodic memory and autonoetic consciousness exhibited a strong temporal gradient extending 30 to 40 y into the past. These results highlight the distinct and critical role of human hippocampal CA1 neurons in autobiographical memory retrieval and for re-experiencing detailed episodic memories.A utobiographical memory is one of the multifaceted forms of human memory that constitutes a major source for selfidentity, self-continuity, and self-awareness of an individual's life. Episodic autobiographical recollection includes conscious awareness for specific episodic situations embedded in time and space, and the ability of mental reliving of episodes of a person's history along the subjective and mental time axis (1). Considering the phenomenological experience of remembering, episodic recollection involving re-experiencing requires autonoetic consciousness in contrast to semantic knowledge of memory, which is associated with noetic consciousness (2).It is generally accepted that the hippocampus plays a critical role in episodic memory, including autobiographical memory, as neuroimaging data show hippocampal activation in autobiographical memory retrieval tasks, supporting that the hippocampus is an integral structure of the autobiographical network (3, 4). The involvement of the hippocampus culminates in the question of the temporal contribution of the hippocampal-neocortical interaction in the consolidation and recollection of remote episodic memory (5). One view, according to the standard model of consolidation, considers the hippocampus as a temporary relay structure that facilitates the transition of newly encoded hippocampus-dependant memory traces to its permanent storage and consolidation in neocortical structures, resulting in hippocampus-independent remote memories (6). This transitory role of the hippocampus is thought to be reflected in the temporal gradient of retrograde amnesia seen in patients with lesions to the medial temporal lobe (MTL). Evidence for this time-limited role of the hippocampus has come from lesion studies of amnestic patients and neuroimaging studies (7,8). In contrast, the multiple trace theory (MTT) postulates a permanent contribution of the hippocampus in retrieving and recollection in terms of a binding module for episodic memories (9). This v...

“…self-ordered sequencing | muscimol | temporal lobe | cognition | nonhuman primate A lthough a role for the hippocampus in navigational spatial memory has been well documented in many species, including humans (1)(2)(3)(4), rodents (5,6), and monkeys (7)(8)(9), a role for hippocampus in nonnavigational spatial memory is less certain. Because nonhuman primates have a close neuroanatomical and behavioral homology to humans, they offer a unique opportunity to assess the neural substrates of spatial memory using nonnavigational tasks.…”

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confidence: 99%

Memory loss in a nonnavigational spatial task after hippocampal inactivation in monkeys

Forcelli

Palchik

Leath³

et al. 2014

The hippocampus has a well-documented role for spatial navigation across species, but its role for spatial memory in nonnavigational tasks is uncertain. In particular, when monkeys are tested in tasks that do not require navigation, spatial memory seems unaffected by lesions of the hippocampus. However, the interpretation of these results is compromised by long-term compensatory adaptation occurring in the days and weeks after lesions. To test the hypothesis that hippocampus is necessary for nonnavigational spatial memory, we selected a technique that avoids long-term compensatory adaptation. We transiently disrupted hippocampal function acutely at the time of testing by microinfusion of the glutamate receptor antagonist kynurenate. Animals were tested on a self-ordered spatial memory task, the Hamilton Search Task. In the task, animals are presented with an array of eight boxes, each containing a food reinforcer; one box may be opened per trial, with trials separated by a delay. Only the spatial location of the boxes serves as a cue to solve the task. The optimal strategy is to open each box once without returning to previously visited locations. Transient inactivation of hippocampus reduced performance to chance levels in a delay-dependent manner. In contrast, no deficits were seen when boxes were marked with nonspatial cues (color). These results clearly document a role for hippocampus in nonnavigational spatial memory in macaques and demonstrate the efficacy of pharmacological inactivation of this structure in this species. Our data bring the role of the hippocampus in monkeys into alignment with the broader framework of hippocampal function.A lthough a role for the hippocampus in navigational spatial memory has been well documented in many species, including humans (1-4), rodents (5, 6), and monkeys (7-9), a role for hippocampus in nonnavigational spatial memory is less certain. Because nonhuman primates have a close neuroanatomical and behavioral homology to humans, they offer a unique opportunity to assess the neural substrates of spatial memory using nonnavigational tasks. However, studies using nonnavigational spatial tasks with nonhuman primates have found little or no effect of hippocampal lesions (10-15).The ability of hippocampal-lesioned monkeys to perform these tasks without impairment has been explained by the reliance on a strategy that is not dependent on hippocampus. Whereas the use of allocentric (world-centered) cues depends on the hippocampus, it is thought that the use of egocentric (body-centered) cues does not. Indeed, it has been suggested that the use of egocentric cues is supported by extrahippocampal substrates including striatum and parietal cortex (15)(16)(17)(18).Following a hippocampal lesion, subjects may learn to resolve a given task by developing a strategy distinct from that used in the presence of an intact hippocampus. Several factors may support this compensatory strategy, including (i) postlesion training or retraining and (ii) postlesion network reorganization (19-21). T...