Biomedical subjects

Robert W Stackman

Publications and source records attributed to Robert W Stackman.

10 recordsLinked to original sources

PubMed2006

Small-conductance Ca2+-activated K+ channel type 2 (SK2) modulates hippocampal learning, memory, and synaptic plasticity.

Apamin-sensitive, small-conductance, Ca2+-activated K+ channels (SK channels) modulate neuronal excitability in CA1 neurons. Blocking all SK channel subtypes with apamin facilitates the induction of hippocampal synaptic plasticity and enhances hippocampal learning. In CA1 dendrites, SK channels are activated by Ca2+ through NMDA receptors and restrict glutamate-mediated EPSPs. Studies of SK channel knock-out mice reveal that of the three apamin-sensitive SK channel subunits (SK1-SK3), only SK2 subunits are necessary for the apamin-sensitive currents in CA1 hippocampal neurons. To determine the specific influence of SK2 channels on hippocampal synaptic plasticity, learning, and memory, we used gene targeting through homologous recombination in embryonic stem cells to generate transgenic mice that overexpress SK2 subunits by 10-fold (SK2+/T). In these mice, the apamin-sensitive current in CA1 neurons was increased by approximately fourfold, relative to wild-type (WT) littermates. In addition, the amplitude of synaptically evoked EPSPs recorded from SK2+/T CA1 neurons increased twice as much in response to SK channel blockade relative to EPSPs recorded from WT CA1 neurons. Consistent with this, SK2 overexpression reduced long-term potentiation after high-frequency stimulation compared with WT littermates and severely impaired learning in both hippocampus- and amygdala-dependent tasks. We conclude that SK2 channels regulate hippocampal synaptic plasticity and play a critical role in modulating mechanisms of learning and memory.

Animals↗

PubMed2006

Chronic dietary alpha-lipoic acid reduces deficits in hippocampal memory of aged Tg2576 mice.

Oxidative stress may play a key role in Alzheimer's disease (AD) neuropathology. Here, the effects of the antioxidant, alpha-lipoic acid (ALA) were tested on the Tg2576 mouse, a transgenic model of cerebral amyloidosis associated with AD. Ten-month old Tg2576 and wild type mice were fed an ALA-containing diet (0.1%) or control diet for 6 months and then assessed for the influence of diet on memory and neuropathology. ALA-treated Tg2576 mice exhibited significantly improved learning, and memory retention in the Morris water maze task compared to untreated Tg2576 mice. Twenty-four hours after contextual fear conditioning, untreated Tg2576 mice exhibited significantly impaired context-dependent freezing. ALA-treated Tg2576 mice exhibited significantly more context freezing than the untreated Tg2576 mice. Assessment of brain soluble and insoluble beta-amyloid levels revealed no differences between ALA-treated and untreated Tg2576 mice. Brain levels of nitrotyrosine, a marker of nitrative stress, were elevated in Tg2576 mice, while F2 isoprostanes and neuroprostanes, oxidative stress markers, were not elevated in the Tg2576 mice relative to wild type. These data indicate that chronic dietary ALA can reduce hippocampal-dependent memory deficits of Tg2576 mice without affecting beta-amyloid levels or plaque deposition.

Aging↗

PubMed2004

Rat head direction cell responses in zero-gravity parabolic flight.

Astronauts working in zero-gravity (0-G) often experience visual reorientation illusions (VRIs). For example, when floating upside down, they commonly misperceive the spacecraft floor as a ceiling and have a reversed sense of direction. Previous studies have identified a population of neurons in the rat's brain that discharge as a function of the rat's head direction (HD) in a gravitationally horizontal plane and is dependent on an intact vestibular system. Our goal was to characterize HD cell discharge under conditions of acute weightlessness. Seven HD cells in the anterior dorsal thalamus were monitored from rats aboard an aircraft in 0-G parabolic flight. Unrestrained rats locomoted in a clear plexiglas rectangular chamber that had wire mesh covering the floor, ceiling, and one wall. The chamber and surrounding visual environment were relatively up-down symmetrical. Each HD cell was recorded across forty 20-s episodes of 0-G. All HD cells maintained a significant direction-specific discharge when the rat was on the chamber floor during the 0-G and also during the hypergravity pull-out periods. Three of five cells also showed direction-specific responses on the wall in 1-G. In contrast, direction-specific discharge was usually not maintained when the rat locomoted on the vertical wall or ceiling in 0-G. The loss of direction-specific firing was accompanied by an overall increase in background firing. However, while the rat was on the ceiling, some cells showed occasional bursts of firing when the rat's head was oriented in directions that were flipped relative to the long axis of symmetry of the chamber compared with the cell's preferred firing direction on the floor. This finding is consistent with what might be expected if the rat had experienced a VRI. These responses indicate that rats maintain a normal allocentric frame of reference in 0-G and 1-G when on the floor, but may lose their sense of directional heading when placed on a wall or ceiling during acute exposures to 0-G.

Animals↗

PubMed2004

On the delay-dependent involvement of the hippocampus in object recognition memory.

The role of the hippocampus in object recognition memory processes is unclear in the current literature. Conflicting results have been found in lesion studies of both primates and rodents. Procedural differences between studies, such as retention interval, may explain these discrepancies. In the present study, acute lidocaine administration was used to temporarily inactivate the hippocampus prior to training in the spontaneous object recognition task. Male C57BL/6J mice were administered bilateral lidocaine (4%, 0.5 microl/side) or aCSF (0.5 microl/side) directly into the CA1 region of the dorsal hippocampus 5 min prior to sample object training, and object recognition memory was tested after a short ( 5 min) or long (24 h) retention interval. There was no effect of intra-hippocampal lidocaine on the time needed for mice to accumulate sample object exploration, suggesting that inactivation of the hippocampus did not affect sample session activity or the motivation to explore objects. Lidocaine-treated mice exhibited impaired object recognition memory, measured as reduced novel object preference, after a 24 h but not a 5 min retention interval. These data support a delay-dependent role for the hippocampus in object recognition memory, an effect consistent with the results of hippocampal lesion studies conducted in rats. However, these data are also consistent with the view that the hippocampus is involved in object recognition memory regardless of retention interval, and that object recognition processes of parahippocampal structures (e.g., perirhinal cortex) are sufficient to support object recognition memory over short retention intervals.

Anesthetics, Local↗

PubMed2003

Hippocampal place cell instability after lesions of the head direction cell network.

The occurrence of cells that encode spatial location (place cells) or head direction (HD cells) in the rat limbic system suggests that these cell types are important for spatial navigation. We sought to determine whether place fields of hippocampal CA1 place cells would be altered in animals receiving lesions of brain areas containing HD cells. Rats received bilateral lesions of anterodorsal thalamic nuclei (ADN), postsubiculum (PoS), or sham lesions, before place cell recording. Although place cells from lesioned animals did not differ from controls on many place-field characteristics, such as place-field size and infield firing rate, the signal was significantly degraded with respect to measures of outfield firing rate, spatial coherence, and information content. Surprisingly, place cells from lesioned animals were more likely modulated by the directional heading of the animal. Rotation of the landmark cue showed that place fields from PoS-lesioned animals were not controlled by the cue and shifted unpredictably between sessions. Although fields from ADN-lesioned animals tended to have less landmark control than fields from control animals, this impairment was mild compared with cells recorded from PoS-lesioned animals. Removal of the prominent visual cue also led to instability of place-field representations in PoS-lesioned, but not ADN-lesioned, animals. Together, these findings suggest that an intact HD system is not necessary for the maintenance of place fields, but lesions of brain areas that convey the HD signal can degrade this signal, and lesions of the PoS might lead to perceptual or mnemonic deficits, leading to place-field instability between sessions.

Animals↗

PubMed2003

Passive transport disrupts directional path integration by rat head direction cells.

A subset of neurons in the rat limbic system encodes head direction (HD) by selectively discharging when the rat points its head in a preferred direction in the horizontal plane. The preferred firing direction is sensitive to the location of landmark cues, as well as idiothetic or self-motion cues (i.e., vestibular, motor efference copy, proprioception, and optic flow). Previous studies have shown that the preferred firing direction remains relatively stable (average shift +/- 18 degrees ) after the rat walks from a familiar environment into a novel one, suggesting that without familiar landmarks, the preferred firing direction can be maintained using idiothetic cues, a process called directional path integration. This study repeated this experiment and manipulated the idiothetic cues available to the rat as it moved between the familiar and novel environment. Motor efference copy/proprioceptive cues were disrupted by passively transporting the animal between the familiar and novel environment. Darkening the room as the animal moved to the novel environment eliminated optic flow cues. HD cell preferred firing directions shifted in the novel environment by an average of 30 degrees after locomotion from the familiar environment with the room lights off; by an average of 70 degrees after passive transport from the familiar environment with the room lights on; and by an average of 67 degrees after passive transport with the room lights off. These findings are consistent with the view that motor efference copy/proprioception cues are important for maintaining the preferred firing direction of HD cells under conditions requiring path integration.

Action Potentials↗

PubMed2003

Prevention of age-related spatial memory deficits in a transgenic mouse model of Alzheimer's disease by chronic Ginkgo biloba treatment.

Alzheimer's disease (AD) is characterized by cognitive decline and deposition of beta-amyloid (Abeta) plaques in cortex and hippocampus. A transgenic mouse AD model (Tg2576) that overexpresses a mutant form of human Abeta precursor protein exhibits age-related cognitive deficits, Abeta plaque deposition, and oxidative damage in the brain. We tested the ability of Ginkgo biloba, a flavonoid-rich antioxidant, to antagonize the age-related behavioral impairment and neuropathology exhibited by Tg2576 mice. At 8 months of age, 16 female Tg2576 and 15 female wild-type (wt) littermate mice were given ad lib access to tap water or Ginkgo biloba (70 mg/kg/day in water). After 6 months of treatment, all mice received Morris water maze training (4 trials/day for 10 days) to assess hippocampal dependent spatial learning. All mice received a 60-s probe test of spatial memory retention 24 h after the 40th trial. Untreated Tg2576 mice exhibited a spatial learning impairment, relative to wt mice, while Ginkgo biloba-treated Tg2576 mice exhibited spatial memory retention comparable to wt during the probe test. Spatial learning was not different between Ginkgo biloba-treated and untreated wt mice. There were no group differences in learning to swim to a visible platform. Soluble Abeta and hippocampal Abeta plaque burden did not differ between the Tg2576 groups. Brain levels of protein carbonyls were paradoxically elevated in Ginkgo biloba-treated mice. These data indicate that chronic Ginkgo biloba treatment can block an age-dependent decline in spatial cognition without altering Abeta levels and without suppressing protein oxidation in a transgenic mouse model of AD.

Aging↗

PubMed2002

Small conductance Ca2+-activated K+ channels modulate synaptic plasticity and memory encoding.

Activity-dependent changes in neuronal excitability and synaptic strength are thought to underlie memory encoding. In hippocampal CA1 neurons, small conductance Ca2+-activated K+ (SK) channels contribute to the afterhyperpolarization, affecting neuronal excitability. In the present study, we examined the effect of apamin-sensitive SK channels on the induction of hippocampal synaptic plasticity in response to a range of stimulation frequencies. In addition, the role of apamin-sensitive SK channels on hippocampal-dependent memory encoding and retention was also tested. The results show that blocking SK channels with apamin increased the excitability of hippocampal neurons and facilitated the induction of synaptic plasticity by shifting the modification threshold to lower frequencies. This facilitation was NMDA receptor (NMDAR) dependent and appeared to be postsynaptic. Mice treated with apamin demonstrated accelerated hippocampal-dependent spatial and nonspatial memory encoding. They required fewer trials to learn the location of a hidden platform in the Morris water maze and less time to encode object memory in an object-recognition task compared with saline-treated mice. Apamin did not influence long-term retention of spatial or nonspatial memory. These data support a role for SK channels in the modulation of hippocampal synaptic plasticity and hippocampal-dependent memory encoding.

Action Potentials↗

PubMed2002

Rats with lesions of the vestibular system require a visual landmark for spatial navigation.

The role of the vestibular system in acquisition and performance of a spatial navigation task was examined in rats. Male Long-Evans rats received sham or bilateral sodium arsanilate-induced vestibular lesions. After postoperative recovery, under partial water-deprivation, rats were trained (16 trials/day) to find a water reward in one corner of a black square enclosure. A cue card fixed to one wall of the enclosure served as a stable landmark cue. The orientation of the rat at the start of each trial was pseudo-randomized such that the task could not be solved by an egocentric response strategy. Rats with vestibular lesions acquired the task in fewer trials than the sham treated control rats. Vestibular lesions did not influence the motivation or motor function necessary to perform the task. Performance of sham rats was maintained during probe trials in which the cue card was removed from the enclosure, while lesioned rats were markedly impaired. Rotation of the cue card (+/-90 degrees ) caused an equivalent shift in corner choice behavior of the lesioned rats. However, sham rats often disregarded the rotated cue card and made place responses. These results suggest that the vestibular lesions disrupt idiothetic navigation or path integration and render navigational behavior critically dependent upon external landmarks. These results are consistent with the navigational abilities of humans with bilateral vestibular dysfunction.

Animals↗

PubMed2002

Hippocampal spatial representations require vestibular input.

The hippocampal formation is essential for forming declarative representations of the relationships among multiple stimuli. The rodent hippocampal formation, including the entorhinal cortex and subicular complex, is critical for spatial memory. Two classes of hippocampal neurons fire in relation to spatial features. Place cells collectively map spatial locations, with each cell firing only when the animal occupies that cell's "place field," a particular subregion of the larger environment. Head direction (HD) cells encode directional heading, with each HD cell firing when the rat's head is oriented in that cell's particular "preferred firing direction." Both landmarks and internal cues (e.g., vestibular, motor efference copy) influence place and HD cell activity. However, as is the case for navigation, landmarks are believed to exert greater influence over place and HD cell activity. Here we show that temporary inactivation of the vestibular system led to the disruption of location-specific firing in hippocampal place cells and direction-specific discharge of postsubicular HD cells, without altering motor function. Place and HD cell activity recovered over a time course similar to that of the restoration of vestibular function. These results indicate that vestibular signals provide an important influence over the expression of hippocampal spatial representations, and may explain the navigational deficits of humans with vestibular dysfunction.

Animals↗