Eugenia Friedman | University of Wisconsin-Madison (original) (raw)

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Papers by Eugenia Friedman

Plos Biology, Jan 1, 2008

How long-term memories are stored is a fundamental question in neuroscience. The first molecular ... more How long-term memories are stored is a fundamental question in neuroscience. The first molecular mechanism for long-term memory storage in the brain was recently identified as the persistent action of protein kinase Mzeta (PKMf), an autonomously active atypical protein kinase C (PKC) isoform critical for the maintenance of long-term potentiation (LTP). PKMf maintains aversively conditioned associations, but what general form of information the kinase encodes in the brain is unknown. We first confirmed the specificity of the action of zeta inhibitory peptide (ZIP) by disrupting long-term memory for active place avoidance with chelerythrine, a second inhibitor of PKMf activity. We then examined, using ZIP, the effect of PKMf inhibition in dorsal hippocampus (DH) and basolateral amygdala (BLA) on retention of 1-d-old information acquired in the radial arm maze, water maze, inhibitory avoidance, and contextual and cued fear conditioning paradigms. In the DH, PKMf inhibition selectively disrupted retention of information for spatial reference, but not spatial working memory in the radial arm maze, and precise, but not coarse spatial information in the water maze. Thus retention of accurate spatial, but not procedural and contextual information required PKMf activity. Similarly, PKMf inhibition in the hippocampus did not affect contextual information after fear conditioning. In contrast, PKMf inhibition in the BLA impaired retention of classical conditioned stimulusunconditioned stimulus (CS-US) associations for both contextual and auditory fear, as well as instrumentally conditioned inhibitory avoidance. PKMf inhibition had no effect on postshock freezing, indicating fear expression mediated by the BLA remained intact. Thus, persistent PKMf activity is a general mechanism for both appetitively and aversively motivated retention of specific, accurate learned information, but is not required for processing contextual, imprecise, or procedural information.

Current Biology, Jan 1, 2004

Introduction and Psychiatry Brain Research Institute Cognitive impairments, especially deficits i... more Introduction and Psychiatry Brain Research Institute Cognitive impairments, especially deficits in learning University of California, Los Angeles and memory, are the hallmark of normal aging; they 2554 Gonda Center, Box 951761 often occur in the absence of neuropathology such as Los Angeles, California 90095 that associated with Alzheimer's disease [1]. Because 2 Cold Spring Harbor Laboratory of the central role that it plays in mammalian learning Cold Spring Harbor, New York 11724 and memory, the hippocampus is thought to be responsible, at least in part, for the age-related cognitive decline that occurs during normal aging [2]. This idea gains Summary support from behavioral experiments demonstrating that aged humans [3], rats [4], and mice [5] perform poorly in Background: Advancing age is typically accompanied

Neuropharmacology, Jan 1, 2001

Previous results have suggested that the Ras signaling pathway is involved in learning and memory... more Previous results have suggested that the Ras signaling pathway is involved in learning and memory. Ras is activated by nucleotide exchange factors, such as the calmodulin-activated guanine-nucleotide releasing factor 1 (Ras-GRF1). To test whether Ras-GRF1 is required for learning and memory, we inactivated the Ras-GRF1 gene in mice. These mutants performed normally in a rota-rod motor coordination task, and in two amygdala-dependent tasks (inhibitory avoidance and contextual conditioning). In contrast the mutants were impaired in three hippocampus-dependent learning tasks: contextual discrimination, the social transmission of food preferences, and the hidden-platform version of the Morris water maze. These studies indicate that Ras-GRF1 plays a role in hippocampal-dependent learning and memory.

Behavioural Brain Research, Jan 1, 1998

Recently, gene targeting and other mouse transgenic techniques have been used to study the cellul... more Recently, gene targeting and other mouse transgenic techniques have been used to study the cellular mechanisms underlying learning and memory mechanisms in the hippocampus. A key assumption of many of these studies is that lesions of the hippocampus have a similar impact on learning and memory in mice and in rats. Here, we used axon-sparing ibotenate lesions to determine whether damage to the hippocampus disrupts spatial learning and contextual conditioning in mice, as it is known to do in rats. Our results demonstrated that hippocampal lesions impair performance in the hidden-platform version of the water maze under a variety of experimental conditions. Neither keeping the start site constant, nor prior training with the visible-platform task fully rescued the spatial learning deficits of the lesioned mice. As previously shown in rats, the lesions left the performance of the mice intact in the visible-platform version of the water maze, indicating that they do not affect all types of learning, and that disruptions of sensory processing or motivation probably did not account for their deficits in the hidden-platform task. In contrast, the very same lesions did not affect either cued or contextual fear conditioning. These results confirm the involvement of the hippocampus in spatial learning in mice, and they also demonstrate that hippocampal-lesioned mice can show contextual fear conditioning. Thus, the behavioral findings presented here are crucial for the interpretation of transgenic experiments with the widely used water maze and fear-conditioning paradigms.

Current Biology, Jan 1, 1996

Background Many studies suggest that long term potentiation (LTP) has a role in learning and memo... more Background Many studies suggest that long term potentiation (LTP) has a role in learning and memory. In contrast, little is known about the function of short-lived plasticity (SLP). Modeling results suggested that SLP could be responsible for temporary memory storage, as in working memory, or that it may be involved in processing information regarding the timing of events. These models predict that abnormalities in SLP should lead to learning deficits. We tested this prediction in four lines of mutant mice with abnormal SLP, but apparently normal LTP – mice heterozygous for a α-calcium calmodulin kinase II mutation (αCaMKII+/−) have lower paired-pulse facilitation (PPF) and increased post-tetanic potentiation (PTP); mice lacking synapsin II (SyII−/−), and mice defective in both synapsin I and synapsin II (SyI/II−/−), show normal PPF but lower PTP; in contrast, mice just lacking synapsin I (SyI−/−) have increased PPF, but normal PTP.Results Our behavioral results demonstrate that α CaMKII+/−, SyII−/− and SyI/II−/− mutant mice, which have decreased PPF or PTP, have profound impairments in learning tasks. In contrast, behavioral analysis did not reveal learning deficits in SyI−/− mice, which have increased PPF.Conclusions Our results are consistent with models that propose a role for SLP in learning, as mice with decreased PPF or PTP, in the absence of known LTP deficits, also show profound learning impairments. Importantly, analysis of the SyI−/− mutants demonstrated that an increase in PPF does not disrupt learning.

Nature Genetics, Jan 1, 1997