Growth points in research on memory and hippocampus.

We present an overview of two of our ongoing projects relating processes in the hippocampus to memory. We are trying to understand why retrograde amnesia occurs after damage to the hippocampus. Our experiments establish the generality of several new retrograde amnesia phenomena that are at odds with the consensus view of the role of the hippocampus in memory. We show in many memory tasks that complete damage to the hippocampus produces retrograde amnesia that is equivalent for recent and remote memories. Retrograde amnesia affects a much wider range of memory tasks than anterograde amnesia. Normal hippocampal processes can interfere with retention of a long-term memory stored outside the hippocampus. We conclude that the hippocampus competes with nonhippocampal systems during memory encoding and retrieval. Finally, we outline a project to understand and manipulate adult hippocampal neurogenesis in order to repair damaged hippocampal circuitry to recover lost cognitive functions. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Organizational changes in cholinergic activity and enhanced visuospatial memory as a function of choline administered prenatally or postnatally or both.

This experiment was an examination of the effects of supplemental dietary choline chloride given prenatally (to the diet of pregnant rats) and postnatally (intubed directly into the stomachs of rat pups) on memory function and neurochemical measures of brain cholinergic activity of male albino rats when they became adults. The data demonstrate that perinatal choline supplementation causes (a) long-term facilitative effects on working and reference memory components of a 12-arm radial maze task, and (b) alternations of muscarinic receptor density as indexed by [–3H]quinuclidinyl benzilate (QNB) binding and choline acetyltransferase (ChAT) levels in the hippocampus and frontal cortex of adult rats. An analysis of the relationship between these organizational changes in brain and memory function indicated that the ChAT-to-QNB ratio in the hippocampus is highly correlated with working memory errors, and this ratio in the frontal cortex is highly correlated with reference memory errors. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Memory retention is modulated by acute estradiol and progesterone replacement.

Ovarian hormones alter spine density of hippocampal granule and pyramidal cells in young adult and aging female rats. (P. Miranda, C. L. Williams, and G. Einstein, 1999; C. S. Woolley, see record 1998-11866-006). The present study used a delay matching-to-place version of the water maze to investigate a behavioral correlate of these hormone-induced changes in hippocampal connectivity in 3- and 8-mo-old female rats. When primed with 10-mg injections of estradiol 72 and 48 hrs before testing, the memory retention of ovariectomized rats was improved compared with retention after priming with oil. A single injection of progesterone maintained the enhancement if testing occurred within 8 hrs of the progesterone injection but not if testing occurred more than 34 hrs after the progesterone injection. These findings indicate that estradiol and progesterone alter memory retention and suggest that these changes may be the result of hormone-induced increased in hippocampal connectivity. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Allopregnanolone concentration in hippocampus of prepubertal rats and female rats throughout estrous cycle

Hippocampus plays an important role in cognition, neuroendocrine function and sexual behaviour. Changes of hippocampal neuropeptide and neurotransmitter concentrations are associated to behavioural changes occurring throughout reproductive life. The present study focused the attention on the presence of a neurosteroid, 5 alpha-pregnan-3 alpha-ol-20-one (termed allopregnanolone) in hippocampus. In particular, hippocampal allopregnanolone concentration in male and female prepubertal rats and in female rats throughout estrous cycle were evaluated. Hippocampal extracts were eluted on high pressure liquid chromatography and allopregnanolone concentration was measured by radioimmunoassay. Prepubertal male and female rats (15 days old) showed highest values which significantly decreased with advancing age (25 and 60 days) (p < 0.01); the lowest hippocampal concentration of allopregnanolone was found in adult rats. Female rats on proestrus morning and afternoon showed an hippocampal allopregnanolone concentration significantly higher than on diestrus or on estrus (p < 0.01), while rats on estrus showed hippocampal allopregnanolone concentration significantly lower than during other days of estrus cycle (p < 0.01). These data indicate differences in hippocampal concentration of allopregnanolone between prepubertal and adult rats and throughout estrous cycle in female rats. This finding suggest a putative role of neurosteroids in the modulation of behavioral changes occurring throughout reproductive life.     

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)     

Arrest of adult hippocampal neurogenesis in mice impairs single- but not multiple-trial contextual fear conditioning.

The role of adult hippocampal neurogenesis in contextual fear conditioning (CFC) is debated. Several studies demonstrated that blocking adult hippocampal neurogenesis in rodents impairs CFC, while several other studies failed to observe an impairment. We sought to determine whether different CFC methods vary in their sensitivity to the arrest of adult neurogenesis. Adult neurogenesis was arrested in mice using low-dose, targeted x-irradiation, and the effects of irradiation were assayed in conditioning procedures that varied in the use of a discrete conditioned stimulus, the number of trials administered, and the final level of conditioning produced. We demonstrate that irradiation impairs CFC in mice when a single-trial CFC procedure is used but not when multiple-trial procedures are used, regardless of the final level of contextual fear produced. In addition, we show that the irradiation-induced deficit in single-trial CFC can be rescued by providing preexposure to the conditioning context. These results indicate that adult hippocampal neurogenesis is required for CFC in mice only when brief training is provided. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The hamster hippocampal slice: II. Neuroendocrine modulation.

Studied effects of exposing golden hamster hippocampal slices to the gonadal steroids estradiol and testosterone and to delta-9-tetra-hydrocannabinol (THC). At 10–20M, estradiol and testosterone acted as facilitatory neuromodulators on hippocampal slices obtained from male and diestrous female hamsters, respectively. At 10–21M, THC facilitated responses in hippocampal slices from males. Implications for the use of the hamster in investigations of the biobehavioral role of steroid modulation of brain excitability are discussed. (14 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Hippocampal and amygdaloid involvement in nonspatial and spatial working memory in rats: Effects of delay and interference.

Parametric manipulations of the task demand were used to examine the role of the hippocampus and amygdala in nonspatial and spatial working memory in male rats. Hippocampal lesions produced an immediate and long-lasting impairment of nonspatial working memory in an operant task. The memory deficits increased as the delay interval and the amount of proactive interference increased. Hippocampal lesions severely impaired spatial working memory in spatial alternation. Extensive postoperative testing reduced the magnitude of impairment of nonspatial but not spatial working memory. Amygdaloid lesions did not impair any aspect of performance in 2 tasks. The results suggest that the hippocampus, but not the amygdala, is involved in working memory and the task demand is a critical determinant for observing impairments of nonspatial working memory following hippocampal lesions. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Posttraining estrogen and memory modulation

The present paper provides a review of recent research carried out in this laboratory investigating the effects of posttraining peripheral and intrahippocampal injection of estradiol on memory in rats, and estradiol-acetylcholine interactions in memory modulation. Ovariectomized rats received an eight-trial training session in a hippocampal-dependent hidden platform water maze task. Immediately following training, rats received a posttraining peripheral or intrahippocampal injection of estradiol-cyclodextrin complex or vehicle. Twenty-four hours later rats were returned to the maze for a retention test session, and latency to escape was used as a measure of memory for the previous day's training. Peripheral posttraining injection of estradiol enhances memory relative to vehicle-treated rats. Injections of estradiol given 2 h posttraining has no effect on retention, indicating a time-dependent effect of estradiol on memory storage processes. A time-dependent memory enhancing effect of posttraining intrahippocampal injections of estradiol has also been observed in both male and ovariectomized female rats. The memory enhancing effect of peripheral posttraining injection of estradiol in ovariectomized rats is blocked by a subeffective dose of the acetylcholine muscarinic receptor antagonist scopolamine, suggesting that estradiol interacts with cholinergic systems in memory modulation. Concurrent peripheral posttraining injection of a subeffective dose of estradiol and a subeffective dose of the cholinergic agonist oxotremorine produces a synergistic memory enhancing effect. The findings suggest that: (1) estradiol selectively influences memory storage independent of an effect on nonmnemonic processes, (2) the hippocampus is a potential neuroanatomical site of action mediating estrogenic effects on memory, and (3) estradiol interacts with cholinergic systems in memory modulation.     

17β-estradiol modifies stress-induced and age-related changes in hippocampal synaptic plasticity.

The female steroid hormone 17β-estradiol enhances synaptic transmission and the magnitude of longterm potentiation (LTP) in adult rodent hippocampal slices. Long-term depression (LTD), another form of synaptic plasticity, occurs more prominently in hippocampal slices from aged rodents. A decrease in LTP has been recorded in hippocampal slices from adult rodents behaviorally stressed just before tissue preparation and electrophysiological recording. Here, the authors test the hypothesis that estrogen modifies synaptic plasticity in both adult and aged rodents, whether behaviorally stressed or not. Our results indicate that estrogen enhances LTP and attenuates LTD, thus producing a protective effect against both aging and stress. These results also provide new approaches that can be used to reverse age and stress-related learning and memory dysfunction. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Selective hippocampal lesions and behavior: Effects of kainic acid lesions on performance of place and cue tasks.

Used kainic acid (KA; 1 and 2 μg/μl) lesions to study the effects of damage to the CA3 cell field and subiculum on performance of complex place and cue tasks by 54 male albino rats. In Exp I, neuroanatomical techniques determined the selectivity of the lesions. In a within-Ss design, Ss in Exp II were trained before the operations to run on an 8-arm radial maze with procedures that involved 2 kinds of learning (place and cue) and 2 memory functions (reference memory and working memory). Interrupting the intrahippocampal circuit by damaging the CA3 cell field with KA had minimal effects on performance; injections into subiculum and complete aspiration lesions of hippocampus resulted in impairments on the place but not the cue task. Only intraventricular injections of KA affected performance on both tasks. Results fail to support either the cognitive map or the working memory theory of hippocampal function. It is suggested that distant damage beyond the immediate area of injection complicates interpretation of the results and may limit the usefulness of KA as a neurotoxin in behavioral investigations. (57 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Cardiorespiratory fitness, hippocampal volume, and frequency of forgetting in older adults.

Objective: The purpose of this study was to extend our earlier work to determine the extent to which cardiorespiratory fitness is associated with the frequency of memory problems via its effects on the hippocampus and spatial working memory. We hypothesized that age, sex, education, body composition, and physical activity were direct determinants of fitness, which, in turn, influenced frequency of forgetting indirectly through hippocampal volume and spatial working memory. Method: We conducted assessments of demographic characteristics, Body Mass Index (BMI), physical activity, cardiorespiratory fitness, hippocampal volume, spatial working memory, and frequency of forgetting in 158 older adults (M age = 66.49). Path analyses within a covariance modeling framework were used to examine relationships among these constructs. Results: Sex, age, BMI, and education were all significant determinants of cardiorespiratory fitness. The hypothesized path models for testing the effects of fitness on frequency of forgetting through hippocampal volume and accuracy and speed of spatial working memory all fit the data well. Conclusions: Our findings suggest that older adults with higher levels of fitness show greater preservation of hippocampal volume, which, in turn, is associated with more accurate and faster spatial memory and fewer episodes of forgetting. Given the proportion of older adults reporting memory problems, it is necessary to determine whether improvements in fitness brought about by physical activity interventions can result in subsequent attenuation of memory problems or potentially in improvements in memory. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Neuroanatomical and cognitive mediators of age-related differences in episodic memory.

Aging is associated with declines in episodic memory. In this study, the authors used a path analysis framework to explore the mediating role of differences in brain structure, executive functions, and processing speed in age-related differences in episodic memory. Measures of regional brain volume (prefrontal gray and white matter, caudate, hippocampus, visual cortex), executive functions (working memory, inhibitory control, task switching, temporal processing), processing speed, and episodic memory were obtained in a sample of young and older adults. As expected, age was linked to reduction in regional brain volumes and cognitive performance. Moreover, neural and cognitive factors completely mediated age differences in episodic memory. Whereas hippocampal shrinkage directly affected episodic memory, prefrontal volumetric reductions influenced episodic memory via limitations in working memory and inhibitory control. Age-related slowing predicted reduced efficiency in temporal processing, working memory, and inhibitory control. Lastly, poorer temporal processing directly affected episodic memory. No direct effects of age on episodic memory remained once these factors were taken into account. These analyses highlight the value of a multivariate approach with the understanding of complex relationships in cognitive and brain aging. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Enhanced sensitivity of the MRL/MpJ mouse to the neuroplastic and behavioral effects of acute and chronic antidepressant treatments.

Adult hippocampal neurogenesis has been implicated in the pathophysiology of depression and in the therapeutic effects of antidepressant drugs. Current immunohistochemical methods that study neurogenesis are time consuming and labor intensive. Therefore, a significantly more rapid flow cytometric method was characterized to measure neurogenesis in the adult mouse brain. The sensitivity of mice to the effects of antidepressant treatments is dependent on genetic background. Thus, studies were conducted comparing the responsiveness of 2 inbred mouse strains, MRL/MpJ and C57BL/6J, to the acute and chronic effects of antidepressants on neurochemistry and behavior. Acutely, MRL/MpJ mice displayed more robust behavioral and neurochemical responses to pharmacologically distinct antidepressants than C57BL/6J mice. Chronic administration of the antidepressant drugs fluoxetine and desipramine produced robust elevations in hippocampal cell proliferation and brain-derived neurotrophic factor (BDNF) protein levels in MRL/MpJ mice. C57BL/6J mice treated similarly with antidepressant drugs were mainly unresponsive on these measures. Mice were tested in the novelty-induced hypophagia (NIH) paradigm to examine a behavioral response associated with chronic, but not acute, antidepressant treatment. Only MRL/MpJ mice were behaviorally responsive to chronic antidepressant administration in the NIH paradigm. The positive effects of chronic antidepressants on hippocampal cell proliferation and BDNF paralleled the ability of these drugs to produce changes in NIH behavior. These studies highlight the advantages of using flow cytometry to study hippocampal neurogenesis and identify the MRL/MpJ mouse as a strain with superior response to antidepressant drug treatments that may lead to a better understanding of the genetics behind antidepressant efficacy and sensitivity. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

On the role of hippocampal connections in the performance of place and cue tasks: Comparisons with damage to hippocampus.

38 male albino Sprague-Dawley rats were trained to run a radial maze with a procedure that involved 2 kinds of learning (place and cue) and 2 memory functions (working and reference) before receiving fimbria-fornix, entorhinal-cortex, dentate-gyrus, mammillary-body, or no lesions to determine behavioral changes following interruption of the main connections of hippocampus and closely related areas. Ss with fimbria-fornix and entorhinal-cortex lesions were impaired on both the place and cue tasks. These Ss suffered a general impairment in working memory on both tasks but were impaired in reference memory only on the place task. Ss with dentate-gyrus and mammillary-body lesions were able to perform the complex place and cue tasks with minimal problems. The present findings are contrasted with those of previous research, which indicate that direct damage to the hippocampus (including all cell fields, alveus, fimbria) results in impaired performance only on place tasks. Taken together, present and past findings indicate that interruption of hippocampal input/output pathways and/or damaging some closely related structures has a greater effect on the behaviors studied than does direct damage to the hippocampus. (24 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Low levels of estradiol facilitate, whereas high levels of estradiol impair, working memory performance on the radial arm maze.

Previous investigations of estradiol's effects on learning and memory yielded equivocal results. This study was designed to determine whether these inconsistencies were due to dose-dependent effects of estradiol on different memory processes. Ovariectomized female rats were injected daily with estradiol benzoate (EB; 0.32, 1.00, or 5.00 μg) or vehicle. Approximately 3 hr after injection, rats were run on a hippocampus-dependent working/reference memory version of the radial arm maze. Total number of working (WME), reference, and combined working/reference memory errors were scored. Compared with vehicle, 1.00 or 5.00 μg EB (high physiological) impaired performance by increasing the number of WME, whereas 0.32 μg EB (low physiological) facilitated performance by decreasing the number of WME. Taken together, these data demonstrate a dose-dependent effect of EB on working memory. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Neurogenesis in the adult human hippocampus

The genesis of new cells, including neurons, in the adult human brain has not yet been demonstrated. This study was undertaken to investigate whether neurogenesis occurs in the adult human brain, in regions previously identified as neurogenic in adult rodents and monkeys. Human brain tissue was obtained postmortem from patients who had been treated with the thymidine analog, bromodeoxyuridine (BrdU), that labels DNA during the S phase. Using immunofluorescent labeling for BrdU and for one of the neuronal markers, NeuN, calbindin or neuron specific enolase (NSE), we demonstrate that new neurons, as defined by these markers, are generated from dividing progenitor cells in the dentate gyrus of adult humans. Our results further indicate that the human hippocampus retains its ability to generate neurons throughout life.     

Effect of perinatal gonadal hormones on selected nonsexual behavior patterns: A critical assessment of the nonhuman and human literature.

Reviews the literature on the influence of perinatal gonadal hormones on adult nonsexual behavior patterns in rodents and primates. Perinatal androgens increase the display of adult aggressive behavior in rodents. No research on primates has investigated the effect of perinatal hormones on fighting per se. Instead, high energy expenditure, a trait associated with masculinity in monkeys, has been studied. Female monkeys treated with prenatal androgen exhibit patterns of energy expenditure similar to those of males. Human females exposed to prenatal androgen have been reported by their parents and themselves to show "tomboyish" behavior (i.e. high levels of energy expenditure in play). The effect of perinatal androgen on maternal behavior in rodents is less clear because both male and female rodents will show all aspects of maternal behavior when presented with newborn animals. Human females exposed to prenatal androgen excess have been reported by their parents and themselves to show low levels of maternalism. To explain why genetic females exposed to prenatal androgens were different from controls in regard to energy expenditure and maternalism, researchers have proposed that the behavior changes were a sequel to a masculinizing effect of androgen on the fetal brain. Alternative explanations to postnatal factors are proposed. The influence of perinatal androgen on IQ is also considered. (3 p ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Hippocampus and memory for food caches in black-capped chickadees.

Black-capped chickadees and other food-storing birds recover their scattered caches by remembering the spatial locations of cache sites. Bilateral hippocampal aspiration reduced the accuracy of cache recovery by chickadees to the chance rate, but it did not reduce the amount of caching or the number of attempts to recover caches. In a second experiment, hippocampal aspiration dissociated performance of a task requiring memory for places from performance of a task requiring memory for cues associated with food, disrupting the former but not the latter. On both tasks, however, hippocampal aspiration increased the frequency of revisiting errors to sites previously searched. These experiments show that the structure in the avian brain that is neuroanatomically and embryologically homologous to the mammalian hippocampus shares some functions with the mammalian hippocampus. The results indicate that memory for places and working memory are both disrupted by hippocampal damage in birds. Finally, it was possible to show that these memory capacities are essential for cache recovery by black-capped chickadees. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Differential effects of a reminder cue on amnesia induced by stimulation of amygdala and hippocampus.

Examined the effects of a footshock reminder (FSR) in restoring memory after discrete electrical brain stimulation in 119 male Long-Evans rats. Ss received low-level bilateral electrical stimulation of either the amygdala or the hippocampus after training in a 1-trial passive avoidance task. Ss receiving stimulation showed amnesia when tested 24 hrs after training. One hour after the retention test, Ss received an FSR. 23 hrs later in a 2nd retention test, hippocampus-stimulated Ss showed recovery of memory, while amygdala-stimulated Ss did not. Stimulated Ss that did not receive an FSR remained amnesic. In addition, the effects of amygdala and hippocampal stimulation applied after the FSR were examined. On the 2nd retention test, amygdala stimulation disrupted the FSR effect, while hippocampal stimulation had no deleterious effects. Data are interpreted from a memory-attribute point of view that suggests that the amygdala and hippocampus may be differentially involved in the processing of particular attributes of the learning task. (39 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)