Catalytic properties of the mitochondrial NADH-ubiquinone oxidoreductase (complex I) and the pseudo-reversible active/inactive enzyme transition

The role of stress, arousal, emotional trauma, and corticosteroid and enkephalin secretion on memory and the hippocampus, and the development of traumatic amnesia and repressed memory syndrome are detailed. Animal and human studies are reviewed. Trauma-induced memory deficits appear to be secondary to abnormal neocortical and hippocampal arousal, and corticosteroid and enkephalin secretion which can induce atrophy or seizures within the hippocampus, suppress hippocampal theta activity and long term potentiation, as well as injure hippocampal pyramidal cells. Predisposing factors include individual, age, and sex differences in arousal, and previous emotional trauma or temporal lobe or hippocampal injury. However, as the amygdala processes and stores emotional experiences in memory, patients may also demonstrate trauma related symptoms, including flashbacks as well as shrinking retrograde amnesia.     

Animal models of memory impairment

Memory impairment in the elderly resembles a mild temporal lobe dysfunction. Alterations in the hippocampal formation are also a probable basis for cognitive deficits in some animal models of ageing. For example, aged rats are impaired in hippocampal-dependent tests of spatial memory. Recent studies have revealed considerable structural integrity in the aged hippocampus, even in aged rats with the most impaired spatial memory. In contrast, atrophy/loss of cholinergic neurons in the basal forebrain and deficiency in cholinergic transduction in hippocampus correlate with the severity of spatial memory impairment in aged rats. This evidence supports the longstanding view that age-related loss of memory has a cholinergic basis. In this context, it is somewhat surprising that the use of a selective cholinergic immunotoxin in young rats to further test this hypothesis has revealed normal spatial memory after removing septo-hippocampal cholinergic neurons. Young rats with immunotoxic lesions, however, have other behavioural impairments in tests of attentional processing. These lines of research have implications for understanding the neurobiological basis of memory deficits in ageing and for selecting an optimal behavioural setting in which to examine therapies aimed at restoring neurobiological function.     

Age-related deficits on the radial maze and in fear conditioning: hippocampal processing and consolidation

Young adult, middle-aged, and old male F-344 rats were assessed for their hippocampal ability. This was accomplished by examining the animals on two different paradigms, each incorporating a simultaneous measure of hippocampal-dependent and -independent processing. The animals were fear conditioned and then tested for retention of the conditioning context and tone. This was followed by an 8-arm radial maze task which combined spatial working and cued reference memory elements. The two paradigms are compared in terms of task demands, potential confounds, and validity for aging studies. The results indicate that the performance of the animals on the two tasks is correlated. Age-related deficits limited to the hippocampal aspects of the above tasks were found, with no deficits found in the analogous but hippocampus-independent aspects of these tasks. The function of the hippocampus in incorporating new memories is time-related. Therefore, the possibility of age-related changes in consolidation was examined. It has previously been shown on the fear conditioning paradigm that the hippocampus is involved in retention of the aversive context for approximately 28 days. In the present study, an attempt was made to test the animals for retention of the conditioning context both early into the period of consolidation (10 days) and after consolidation should have been completed (52 days). The results indicate that, initially, the old animals show comparable retention to young rats. When examined later, young animals showed a stronger retention of the conditioning context than they had previously. The aged rats, however, did not seem to benefit from this additional period of time and in fact showed a decrease in retention of the conditioning context. The data are interpreted in terms of consolidation, alternative explanations of the data are presented, and suggestions are given for future research. Finally, the implications of such age-related changes in hippocampal consolidation on learning and memory are discussed.     

An isocratic high performance liquid chromatography (HPLC) assay for moxifloxacin, a new 8-methoxyquinolone

OBJECTIVE: Studies have shown memory deficits among combat veterans with posttraumatic stress disorder (PTSD); however, high rates of comorbid conditions, including alcoholism, make it difficult to definitively associate these findings with the PTSD diagnosis. In this study the authors examined memory functioning among rape survivors without alcoholism or substance abuse but with PTSD. METHOD: Rape victims with (N = 15) and without (N = 16) PTSD were compared to age- and education-matched nontraumatized comparison subjects (N = 16) on measures of learning and memory. RESULTS: The subjects with PTSD performed significantly worse than the other groups on delayed free recall. The deficits were ameliorated by cueing and recognition testing. CONCLUSIONS: Recall deficits in noncombat PTSD patients strengthen the theory that memory deficits are associated with the PTSD diagnosis. The deficits were mild and were not attributable to comorbid depression, anxiety, or substance abuse.     

Hippocampal volume is associated with memory but not monmemory cognitive performance in patients with mild cognitive impairment

Mild cognitive impairment (MCI) appears to be a transitional stage in the development of Alzheimer's disease (AD). Patients with MCI show impaired memory performance and hippocampal atrophy relative to normal elderly controls. Prior studies indicate that the degree of hippocampal atrophy in MCI patients predicts conversion to AD. In contrast to patients with MCI who have deficits primarily in memory, AD patients have clinically evident impairments in both memory and nonmemory cognitive domains. One explanation for the observation that a smaller hippocampal volume predicts conversion to AD might be that hippocampal atrophy is associated with early impairment in nonmemory cognitive areas as well as memory. A link between hippocampal volume and nonmemory function could occur if hippocampal atrophy was correlated with AD pathology in other brain regions. We therefore sought to determine the relationship of hippocampal volume with performance on memory and nonmemory tasks in patients with MCI. Although we found a significant correlation between hippocampal volume and memory performance, we did not find a significant correlation between hippocampal volume and nonmemory performance. We conclude that the relationship between hippocampal volume and risk of AD is likely tied to reduced memory performance and not associated with impairment in nonmemory cognitive domains.     

Preserved neuron number in the hippocampus of aged rats with spatial learning deficits

Hippocampal neuron loss is widely viewed as a hallmark of normal aging. Moreover, neuronal degeneration is thought to contribute directly to age-related deficits in learning and memory supported by the hippocampus. By taking advantage of improved methods for quantifying neuron number, the present study reports evidence challenging these long-standing concepts. The status of hippocampal-dependent spatial learning was evaluated in young and aged Long-Evans rats using the Morris water maze, and the total number of neurons in the principal cell layers of the dentate gyrus and hippocampus was quantified according to the optical fractionator technique. For each of the hippocampal fields, neuron number was preserved in the aged subjects as a group and in aged individuals with documented learning and memory deficits indicative of hippocampal dysfunction. The findings demonstrate that hippocampal neuronal degeneration is not an inevitable consequence of normal aging and that a loss of principal neurons in the hippocampus fails to account for age-related learning and memory impairment. The observed preservation of neuron number represents an essential foundation for identifying the neurobiological effects of hippocampal aging that account for cognitive decline.     

Stress: metaplastic effects in the hippocampus

Memory impairments, which occur regularly across species as a result of aging, disease and psychological insults (for example, stress), constitute a useful area for investigation into the neurobiological basis of learning and memory. Memory researchers have identified the hippocampus as a crucial brain structure involved in key aspects of memory formation. The most widely accepted putative mechanisms of memory storage in this structure are LTP and LTD. The hippocampus is enriched with receptors for corticosterone (a glucocorticoid hormone released in response to stress) and it plays a role in glucocorticoid negative feedback and, therefore, some hippocampal functioning might be particularly susceptible to stress. In support of this view, stress-induced modifications in learning, synaptic plasticity and endangerment of neurons have been seen in the hippocampus. Stress and glucocorticoids appear to exert a metaplastic effect through the modulation of Ca2+ levels. We propose a synaptic model that provides a conceptual scaffold to structure our understanding of the manifold actions of stress on the hippocampus. Accordingly, we suggest that stress-induced metaplasticity could disrupt Ca2+ homeostasis and thus endanger hippocampal neurons.     

Longitudinal MRI and cognitive change in healthy elderly.

Cross-sectional studies of normal aging indicate an association between memory and hippocampal volume, and between executive functioning and subcortical-frontal circuits. Much less is known, however, about the relationship between longitudinal MRI changes and cognitive decline. The authors hypothesized that longitudinal change in memory would be best predicted by change in hippocampal volumes, whereas change in executive functioning would be best predicted by cortical atrophy and progression of MRI markers of cerebrovascular disease. For this study, 50 healthy elderly subjects underwent structural MRI and cognitive testing at baseline and again at follow-up, with a mean follow-up interval of 45 months. Volumetric MRI measures were hippocampus, cortical gray matter, white matter signal hyperintensity (WMSH), and lacunae. Neuropsychological measures were psychometrically robust composite scores of episodic memory (MEM) and executive functioning (EXEC). Hierarchical multiple regression indicated that a decrease in hippocampus was associated with a decline in MEM, whereas decreased cortical gray matter and increased WMSH were independently associated with a decline in EXEC. Results suggest that in normal aging, cognitive functioning declines as cortical gray matter and hippocampus decrease, and WMSH increases. The association between WMSH and EXEC further highlights the cognitive sequealae associated with cerebrovascular disease in normal elderly. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Exploring prefrontal cortical memory mechanisms with eyeblink conditioning.

Several studies in nonhuman primates have shown that neurons in the dorsolateral prefrontal cortex have activity that persists throughout the delay period in delayed matching to sample tasks, and age-related changes in the microcolumnar organization of the prefrontal cortex are significantly correlated with age-related declines in cognition. Activity that persists beyond the presentation of a stimulus could mediate working memory processes, and disruption of those processes could account for memory deficits that often accompany the aging process. These potential memory and aging mechanisms are being systematically examined with eyeblink conditioning paradigms in nonprimate mammalian animal models including the rabbit. The trace version of the conditioning paradigm is a particularly good system to explore declarative memory since humans do not acquire trace conditioning if they are unable to become cognitively aware of the association between a conditioning tone and an airpuff to the eye. This conditioning paradigm has been used to show that the hippocampus and cerebellum interact functionally since both conditioned responses and conditioned hippocampal pyramidal neuron activity are abolished following lesions of the cerebellar nuclei and since hippocampal lesions prevent or abolish trace conditioned blinks. However, because there are no direct connections between the hippocampal formation and the cerebellum, and because the hippocampus is not necessary for trace conditioning after a period of consolidation has elapsed, we and others have been examining the prefrontal cortex for its role in forebrain-dependent trace eyeblink conditioning. This review examines some of the literature which suggests that the prefrontal cortex serves to orchestrate a neuronal network that interacts with the cerebellum to mediate adaptively timed conditioned responses. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Effects of aging on the neural correlates of successful item and source memory encoding.

To investigate the neural basis of age-related source memory (SM) deficits, young and older adults were scanned with fMRI while encoding faces, scenes, and face-scene pairs. Successful encoding activity was identified by comparing encoding activity for subsequently remembered versus forgotten items or pairs. Age deficits in successful encoding activity in hippocampal and prefrontal regions were more pronounced for SM (pairs) as compared with item memory (faces and scenes). Age-related reductions were also found in regions specialized in processing faces (fusiform face area) and scenes (parahippocampal place area), but these reductions were similar for item and SM. Functional connectivity between the hippocampus and the rest of the brain was also affected by aging; whereas connections with posterior cortices were weaker in older adults, connections with anterior cortices, including prefrontal regions, were stronger in older adults. Taken together, the results provide a link between SM deficits in older adults and reduced recruitment of hippocampal and prefrontal regions during encoding. The functional connectivity findings are consistent with a posterior-anterior shift with aging previously reported in several cognitive domains and linked to functional compensation. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Estrogen and basal forebrain cholinergic neurons: implications for brain aging and Alzheimer's disease-related cognitive decline

Recent studies suggest that estrogen replacement therapy can reduce the risk and severity of Alzheimer's disease (AD)-related dementia in postmenopausal women. Many different mechanisms by which estrogen therapy may help to reduce the risk and severity of AD-related pathophysiology have been proposed. Recent animal studies suggest that one way in which estrogen replacement may help to reduce cognitive deficits associated with aging and AD is by enhancing the functional status of cholinergic projections to the hippocampus and cortex. Here we review the evidence that estrogen is important in the maintenance of cholinergic neurons projecting to the hippocampus and cortex and that estrogen replacement can enhance the functional status of these neurons, as well as reduce cognitive deficits associated with muscarinic cholinergic impairment. Based on these studies, we conclude that, in animals, short-term treatment with physiological levels of estrogen, or estrogen and progesterone, has significant positive effects on cholinergic neurons in the medial septum and nucleus basalis magnocellularis and on their projections to the hippocampus and cortex. We hypothesize that similar effects in humans may help delay the decline in basal forebrain cholinergic function associated with aging and AD and thereby reduce the risk and severity of AD-related dementia in postmenopausal women.     

Clinical and magnetic resonance imaging correlates of hypothalamic-pituitary-adrenal axis function in depression and Alzheimer's disease

BACKGROUND: An age-related dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is well recognised in animals, but still remains controversial in humans. There is increasing interest that raised corticosteroid levels, due to activation of the HPA axis, may cause both depressive symptoms and cognitive impairments. Steroid effects on cognition may be via the hippocampus, a major site of corticosteroid action and an important structure involved in learning and memory. METHOD: To investigate this further, we examined the relationship between the dexamethasone suppression test, cognitive function, depressive symptoms and hippocampal atrophy on magnetic resonance imaging (MRI) in 32 normal controls, 49 subjects with NINCDS/ADRDA Alzheimer's disease and 51 patients with DSM-III-R Major Depression. RESULTS: Controlling for differences in dexamethasone concentrations, post-dexamethasone cortisol levels were related to advancing age in controls and depressed subjects. However, among subjects with Alzheimer's disease, post-dexamethasone cortisol levels were independently associated with both minor depressive symptoms and hippocampal atrophy on MRI. CONCLUSION: An association between advancing age and increased HPA axis dysregulation is supported for controls and depressed subjects. In Alzheimer's disease, HPA axis changes were associated with depressive symptoms and hippocampal atrophy. Longitudinal studies are now needed to determine the causal direction of these associations.     

Effects of selective neonatal hippocampal lesions on tests of object and spatial recognition memory in monkeys.

Earlier studies in monkeys have reported mild impairment in recognition memory after nonselective neonatal hippocampal lesions. To assess whether the memory impairment could have resulted from damage to cortical areas adjacent to the hippocampus, we tested adult monkeys with neonatal focal hippocampal lesions and sham-operated controls in three recognition tasks: delayed nonmatching-to-sample, object memory span, and spatial memory span. Further, to rule out that normal performance on these tasks may relate to functional sparing following neonatal hippocampal lesions, we tested adult monkeys that had received the same focal hippocampal lesions in adulthood and their controls in the same three memory tasks. Both early and late onset focal hippocampal damage did not alter performance on any of the three tasks, suggesting that damage to cortical areas adjacent to the hippocampus was likely responsible for the recognition impairment reported by the earlier studies. In addition, given that animals with early and late onset hippocampal lesions showed object and spatial recognition impairment when tested in a visual paired comparison task, the data suggest that not all object and spatial recognition tasks are solved by hippocampal-dependent memory processes. The current data may not only help explain the neural substrate for the partial recognition memory impairment reported in cases of developmental amnesia, but they are also clinically relevant given that the object and spatial memory tasks used in monkeys are often translated to investigate memory functions in several populations of human infants and children in which dysfunction of the hippocampus is suspected. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Ionizing radiation impairs the formation of trace fear memories and reduces hippocampal neurogenesis.

Long-term cognitive impairments are a feared consequence of therapeutic cranial irradiation in children as well as adults. Studies in animal models suggest that these deficits may be associated with a decrease in hippocampal granule cell proliferation and survival. In the present study the authors examined whether whole brain irradiation would affect trace fear conditioning, a hippocampal-dependent task. Preadolescent (postnatal Day 21, PD 21), adolescent (PD 50), and postadolescent (PD 70) rats received single doses of 0 Gray (Gy), 0.3 Gy, 3 Gy, or 10 Gy whole brain irradiation. Three months after radiation treatment, a significant dose-dependent decrease in bromo-deoxyuridine positive cells was observed. Irradiation produced a dose-dependent decrease in freezing in response to the conditioned stimulus in all age groups. Interestingly, the authors found no differences in context freezing between irradiated and control groups. Further, there were no differences in delay fear memories, which are independent of hippocampus function. Our results strongly indicate that irradiation impairs associative memories dependent on hippocampus and this deficit is accompanied by a decrease in granule cell neurogenesis indicating that these cells may be involved in normal hippocampal memory function. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

New routes and formulations for allergen-specific immunotherapy

Altered calcium (Ca2+) homeostasis is thought to play a key role in aging and neuropathology resulting in memory deficits. Several forms of hippocampal synaptic plasticity are dependent on Ca2+, providing a potential link between altered Ca2+ homeostasis and memory deficits associated with aging. The current study reviews evidence for Ca2+ dysregulation during aging which could interact with Ca(2+)-dependent synaptic plasticity. The authors suggest that changes in Ca2+ regulation could adjust the thresholds for synaptic modification, favoring processes for depression of synaptic strength during aging.     

Human hippocampal activation in the delayed matching-and nonmatching-to-sample memory tasks: An event-related functional MRI approach.

The delayed matching-to-sample (DMS) and delayed nonmatching-to-sample (DNMS) memory tasks are standard tools used to probe visual recognition memory in human and nonhuman primates. Previous research indicates that structures within the medial temporal lobe, including the hippocampus, make up a crucial memory circuit for successful performance on these tasks. In the present investigation, event-related functional magnetic resonance imaging was used to examine activation in the hippocampus proper during these memory tasks relative to a perceptuomotor task involving the same stimuli. The results indicate that both memory tasks elicited greater activation in the right hippocampus during the encoding phase. These findings are consistent with the work from human patients and animal studies, indicating hippocampal involvement in the DMS and DNMS tasks. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Neuropsychological functioning in posttraumatic stress disorder and alcohol abuse.

Studies have shown differences in neuropsychological functioning between groups with posttraumatic stress disorder (PTSD) and control participants. Because individuals with PTSD often have a history of comorbid alcohol abuse, the extent to which an alcohol confound is responsible for these differences remains a concern. The current study compares neuropsychological testing scores in 4 groups of veterans with and without PTSD (PTSD+ and PTSD-, respectively) and with and without a history of alcohol abuse (ETOH+ and ETOH-, respectively): n for PTSD+/ETOH- = 30, n for PTSD+/ETOH- = 37, n for PTSD-/ETOH+ = 30, and n for PTSD-/ETOH- = 31. Results showed that PTSD, when alcohol, educational level, vocabulary, and depression are controlled for, was associated with decreased verbal memory, attention, and processing speed performance. Alcohol abuse history was associated with decreased visual memory performance. By controlling for alcohol and depression, the authors can more conclusively demonstrate that verbal memory and attention differences are associated with PTSD. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Preserved negative patterning and impaired spatial learning in pigeons (Columba livia) with lesions of the hippocampus.

Pigeons (Columba livia) with bilateral electrolytic lesions of the hippocampus and area parahippocampalis were compared with control pigeons on 2 tasks: negative patterning and delayed spatial alternation. Negative patterning demands configural stimulus representations for its successful solution. The only effect of hippocampal lesions on this task was an increased response rift to the rewarded stimuli. On the delayed spatial alternation task, hippocampal birds showed deficits relative to controls. Differences in the results of prior studies on negative patterning appear to be due to different response requirements to the nonreinforced stimuli. These results are consistent with prior work with rats and suggest that the avian hippocampus is essential for spatial memory and response inhibition but is not involved in configural learning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)