Huimin Wan

Different contributions of the hippocampus and perirhinal cortex to recognition memory

Brain regions involved in visual recognition memory, including the hippocampus, have been investigated by measuring differential neuronal activation produced by novel and familiar pictures. Novel and familiar pictures were presented simultaneously, one to each eye, using a paired viewing procedure. Differential neuronal activation was determined using immunohistochemistry for the protein products of c-fos as an imaging technique. The results establish that the regions of the rat brain associated with discriminating the novelty or familiarity of an individual item (such as a single object) differ from those responding to a spatial array of items (such as a scene). Perirhinal cortex and area TE of the temporal lobe are activated significantly more by pictures of novel than of familiar individual objects, but the hippocampus is not differentially activated. In contrast, pictures of novel arrangements of familiar items produce significantly greater activation than familiar arrangements of these items in postrhinal cortex and subfield CA1 of the hippocampus but significantly less activation in the dentate gyrus and subiculum; perirhinal cortex and area TE are not differentially activated. Thus, the hippocampus is importantly involved in processing information essential to recognition memory concerning the relative familiarity of arrangements of items, as needed for episodic memory of scenes, whereas the perirhinal cortex processes such information for individual items.

Fos imaging reveals differential neuronal activation of areas of rat temporal cortex by novel and familiar sounds

To provide information about the possible regions involved in auditory recognition memory, this study employed an imaging technique that has proved valuable in the study of visual recognition memory. The technique was used to image populations of neurons that are differentially activated by novel and familiar auditory stimuli, thereby paralleling previous studies of visual familiarity discrimination. Differences evoked by novel and familiar sounds in the activation of neurons were measured in different parts of the rat auditory pathway by immunohistochemistry for the protein product (Fos) of the immediate early gene c‐fos. Significantly higher counts of stained neuronal nuclei (266 ± 21/mm2) were evoked by novel than by familiar sounds (192 ± 17/mm2) in the auditory association cortex (area Te3; AudA). No such significant differences were found for the inferior colliculus, primary auditory cortex, postrhinal cortex, perirhinal cortex (PRH), entorhinal cortex, amygdala or hippocampus. These findings are discussed in relation to the results of lesion studies and what is known of areas involved in familiarity discrimination for visual stimuli. Differential activation is produced by novel and familiar individual stimuli in sensory association cortex for both auditory and visual stimuli, whereas the PRH is differentially activated by visual but not auditory stimuli. It is suggested that this latter difference is related to the nature of the particular auditory and visual stimuli used.

Benzodiazepine impairment of perirhinal cortical plasticity and recognition memory

Benzodiazepines, including lorazepam, are widely used in human medicine as anxiolytics or sedatives, and at higher doses can produce amnesia. Here we demonstrate that in rats lorazepam impairs both recognition memory and synaptic plastic processes (long‐term depression and long‐term potentiation). Both impairments are produced by actions in perirhinal cortex. The findings thus establish a mechanism by means of which benzodiazepines impair recognition memory. The findings also strengthen the hypotheses that the familiarity discrimination component of recognition memory is dependent on reductions in perirhinal neuronal responses when stimuli are repeated and that these response reductions are due to a plastic mechanism also used in long‐term depression.

Delayed Intrinsic Activation of an NMDA-Independent CaM-kinase II in a Critical Time Window Is Necessary for Late Consolidation of an Associative Memory

Calcium/calmodulin-dependent kinases (CaM-kinases) are central to various forms of long-term memory (LTM) in a number of evolutionarily diverse organisms. However, it is still largely unknown what contributions specific CaM-kinases make to different phases of the same specific type of memory, such as acquisition, or early, intermediate, and late consolidation of associative LTM after classical conditioning. Here, we investigated the involvement of CaM-kinase II (CaMKII) in different phases of associative LTM induced by single-trial reward classical conditioning in Lymnaea, a well established invertebrate experimental system for studying molecular mechanisms of learning and memory. First, by using a general CaM-kinase inhibitor, KN-62, we found that CaM-kinase activation was necessary for acquisition and late consolidation, but not early or intermediate consolidation or retrieval of LTM. Then, we used Western blot-based phosphorylation assays and treatment with CaMKIINtide to identify CaMKII as the main CaM-kinase, the intrinsic activation of which, in a critical time window (∼24 h after learning), is central to late consolidation of LTM. Additionally, using MK-801 and CaMKIINtide we found that acquisition was dependent on both NMDA receptor and CaMKII activation. However, unlike acquisition, CaMKII-dependent late memory consolidation does not require the activation of NMDA receptors. Our new findings support the notion that even apparently stable memory traces may undergo further molecular changes and identify NMDA-independent intrinsic activation of CaMKII as a mechanism underlying this “lingering consolidation.” This process may facilitate the preservation of LTM in the face of protein turnover or active molecular processes that underlie forgetting.

The effects of L-AP4 and l-serine-O-phosphate on inhibition in primary somatosensory cortex of the adult rat in vivo

The effects of two iontophoretically applied Group III mGluR agonists were studied on the inhibition in neocortex produced by natural stimulation of vibrissae. The agonists L-AP4 and L-serine-O-phosphate (L-SOP) were shown to produce qualitatively similar effects on the inhibition. Forty-four percent of neurones (total n = 57) displayed disinhibition during application of the agonists. The disinhibitory effects often outlasted the offset of the agonist application by at least 10 min. Concurrent application of the mGluR antagonist (+)-alpha-methyl-4-carboxyphenylglycine ((+)-MCPG) appeared to reverse the disinhibitory effects of L-AP4 and L-SOP in 3 out of 5 neurones tested. However (+)-MCPG itself was found to have disinhibitory effects in some neurones. Some neurones (n = 7) showed increases in inhibition during either L-AP4 or L-SOP application. These appeared most pronounced in those neurones where the initial (pre-drug) inhibition was minimal, perhaps suggesting that the agonists were disinhibiting a local disinhibition. The data obtained in the experiments suggest that the disinhibitory effects are mediated by a heteroreceptor on inhibitory terminals, action at which depresses the release of inhibitory transmitter. The possible role of the modulation of inhibition by presynaptic mGluRs is discussed.

pT305-CaMKII stabilizes a learning-induced increase in AMPA receptors for ongoing memory consolidation after classical conditioning.

The role of CaMKII in learning-induced activation and trafficking of AMPA receptors (AMPARs) is well established. However, the link between the phosphorylation state of CaMKII and the agonist-triggered proteasomal degradation of AMPARs during memory consolidation remains unknown. Here we describe a novel CaMKII-dependent mechanism by which a learning-induced increase in AMPAR levels is stabilized for consolidation of associative long-term memory. Six hours after classical conditioning the levels of both autophosphorylated pT305-CaMKII and GluA1 type AMPAR subunits are significantly elevated in the ganglia containing the learning circuits of the snail Lymnaea stagnalis. CaMKIINtide treatment significantly reduces the learning-induced elevation of both pT305-CaMKII and GluA1 levels and impairs associative long-term memory. Inhibition of proteasomal activity offsets the deleterious effects of CaMKIINtide on both GluA1 levels and long-term memory. These findings suggest that increased levels of pT305-CaMKII play a role in AMPAR dependent memory consolidation by reducing proteasomal degradation of GluA1 receptor subunits.

Group II metabotropic glutamate receptors reduce excitatory but not inhibitory neurotransmission in rat barrel cortex in vivo

Group II metabotropic (mGlu) receptors are known to play an important role in regulating the release of excitatory transmitter in a number of brain areas. Previous experiments demonstrated that (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) depressed excitatory transmission in the adult rat barrel cortex. Here we show, using in vivo extracellular single unit recordings and iontophoretic application of drugs, that selective activation of Group II mGlu receptors depresses excitatory but not inhibitory transmission. The selective Group II receptor agonist (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (2R,4R-APDC) had similar depressant effects to 1S,3R-ACPD on tactile evoked responses of rapidly adapting neurons. The depressant effects were seen on shorter latency (<12 ms) responses, were most pronounced in layers 3-4 (and 5b for 2R,4R-APDC only), and were reversibly antagonized by the Group II receptor antagonist (2S)-alpha-ethylglutamic acid (EGLU) relative to depressions produced by iontophoretic GABA. Where 1S,3R-ACPD and 2R,4R-APDC depressed excitatory transmission, there was little or no effect on postsynaptic excitations produced by iontophoretic AMPA--a result that supports a presynaptic location of Group II receptors on excitatory terminals. To assess the possible involvement of Group II mGlu receptors in the modulation of inhibition, we studied the effect of iontophoretic 1S,3R-ACPD in a condition-test protocol. The results contrasted markedly from those previously observed using the Group III agonist L(+)-2-amino-4-phosphonobutyric acid in that activation of Group II receptors using 1S,3R-ACPD did not modulate inhibition. Therefore our results show that Group II mGlu receptors play an important role in modulating excitatory, but not inhibitory, transmission. We propose that the Group II mGlu receptors are located on excitatory terminals, and act as autoreceptors. Their role appears to be important in the early stages of cortical processing, by keeping excitatory inputs within specified physiological limits, and possibly by mediating depression evidenced during synaptic plasticity.