Wolfram Wetzel

Interleukin-6: a cytokine to forget

It is known that proinflammatory cytokines such as interleukin‐6 (IL‐6) are expressed in the central nervous system (CNS) during disease conditions and affect several brain functions including memory and learning. In contrast to these effects observed during pathological conditions, here we describe a physiological function of IL‐6 in the “healthy” brain in synaptic plasticity and memory consolidation. During long‐term potentiation (LTP) in vitro and in freely moving rats, IL‐6 gene expression in the hippocampus was substantially increased. This increase was long lasting, specific to potentiation, and was prevented by inhibition of N‐methyl‐D‐aspartate receptors with (±)‐2‐amino‐5‐phosphonopentanoic acid (AP‐5). Blockade of endogenous IL‐6 by application of a neutralizing anti‐IL6 antibody 90 min after tetanus caused a remarkable prolongation of LTP. Consistently, blockade of endogenous IL‐6, 90 min after hippocampus‐dependent spatial alternation learning resulted in a significant improvement of long‐term memory. In view of the suggested role of LTP in memory formation, these data implicate IL‐6 in the mechanisms controlling the kinetics and amount of information storage.

A cytokine network involving brain-borne IL-1β, IL-1ra, IL-18, IL-6, and TNFα operates during long-term potentiation and learning

We have previously shown that long-term potentiation (LTP) induces hippocampal IL-1β and IL-6 over-expression, and interfering their signalling either inhibits or supports, respectively, LTP maintenance. Consistently, blockade of endogenous IL-1 or IL-6 restricts or favours hippocampal-dependent memory, effects that were confirmed in genetically manipulated mice. Since cytokines are known for their high degree of mutual crosstalk, here we studied whether a network of cytokines with known neuromodulatory actions is activated during LTP and learning. We found that, besides IL-1β and IL-6, also IL-1 receptor antagonist (IL-1ra) and IL-18, but not TNFα are over-expressed during LTP maintenance in freely moving rats. The increased expression of these cytokines is causally related to an increase in synaptic strength since it was abrogated when LTP was interfered by blockade of NMDA-glutamate receptors. Likewise, IL-1 and IL-6 were found to be over-expressed in defined regions of the hippocampus during learning a hippocampus-dependent task. However, during learning, changes in IL-18 were restricted to the dorsal hippocampus, and no differences in TNFα and IL1-ra expression were noticed in the hippocampus. Noticeably, IL-1ra transcripts were significantly reduced in the prefrontal cortex. The relation between cytokine expression and learning was causal because such changes were not observed in animals from a pseudo-trained group that was subject to the same manipulation but could not learn the task. Taken together with previous studies, we conclude that activation of a cytokine network in the brain is a physiologic relevant phenomenon not only for LTP maintenance but also for certain types of learning.

Right auditory cortex lesion in Mongolian gerbils impairs discrimination of rising and falling frequency-modulated tones

Mongolian gerbils (Meriones unguiculatus) were trained in a shuttle box to discriminate the direction in frequency-modulated tones (FM). Whereas control animals easily acquired FM discrimination, animals with auditory cortex lesion on the right side showed considerable difficulties in learning this task. The discrimination performance of gerbils with left auditory cortex lesion, however, was not different from controls. This study, suggesting that the right auditory cortex plays a dominant role in FM discrimination learning in gerbils, describes a useful animal model for investigation of the basic mechanisms underlying hemispheric asymmetries in auditory perception.

Global versus local processing of frequency-modulated tones in gerbils: An animal model of lateralized auditory cortex functions

Hemispheric asymmetries of speech and music processing might arise from more basic specializations of left and right auditory cortex (AC). It is not clear, however, whether such asymmetries are unique to humans, i.e., consequences of speech and music, or whether comparable lateralized AC functions exist in nonhuman animals, as evolutionary precursors. Here, we investigated the cortical lateralization of perception of linearly frequency-modulated (FM) tones in gerbils, a rodent species with human-like low-frequency hearing. Using a footshock-reinforced shuttle-box avoidance go/no-go procedure in a total of 178 gerbils, we found that (i) the discrimination of direction of continuous FM (rising versus falling sweeps, 250-ms duration) was impaired by right but not left AC lesions; (ii) the discrimination of direction of segmented FM (50-ms segments, 50-ms silent gaps, total duration 250 ms) was impaired by bilateral but not unilateral AC lesions; (iii) the discrimination of gap durations (10–30 ms) in segmented FM was impaired by left but not right AC lesions. AC lesions before and after training resulted in similar effects. Together, these experiments suggest that right and left AC, even in rodents, use different strategies in analyzing FM stimuli. Thus, the right AC, by using global cues, determines the direction of continuous and segmented FM but cannot discriminate gap durations. The left AC, by using local cues, discriminates gap durations and determines FM direction only when additional segmental information is available.

Categorical discrimination of direction in frequency-modulated tones by Mongolian gerbils

Discrimination of the direction of linearly frequency-modulated tones (FMs) was investigated in adult Mongolian gerbils (Meriones unguiculatus) using a footshock motivated shuttle box avoidance go/no go procedure. Symmetric pairs of FMs with frequency linearly increasing with time (ascending FMs) and with frequency linearly decreasing with time (descending FMs) were used as conditioned stimuli, CS+ and CS-, respectively. Stimuli were presented in randomized order in daily sessions over a period of several months. After a number of sessions, the set of conditioned stimuli was changed with respect to frequency range, steepness of modulation and duration. In experiment 1, we observed that gerbils could discriminate between the ascending 2-4 kHz CS+ and the descending 4-2 kHz CS- after a training period of 10-15 days. In experiment 2, we used FM pairs of six other frequency ranges in successive sessions (6-13; 1-2; 13-25; 0.5-1; 3 6; 0.25 0.5 kHz). We found that in the final session the last FM pair (0.25-0.5 kHz) was discriminated already after 3-4 days. Experiment 3 showed that the animals were able to discriminate five of the FM pairs learned in the separate sessions of experiment 2 (i.e. 10 different stimuli) when they were given in randomized order during one training session. In experiment 4, novel FM pairs (not heard before) and familiar FM pairs (trained in experiments 1-3) were presented within one session. It was found that, except for FMs of very short duration and small frequency range, novel FMs were discriminated according to their modulation direction. These results show that Mongolian gerbils are able to discriminate FM tones by modulation direction and, after familiarization with a number of different FM pairs, transfer the ascending-descending concept to stimuli not heard before.

Differential Neuromodulation of Acquisition and Retrieval of Avoidance Learning by the Lateral Habenula and Ventral Tegmental Area

Several studies suggest an opponent functional relationship between the lateral habenula (LHb) and the ventral tegmental area (VTA). Previous work has linked LHb activation to the inhibition of dopaminergic neurons during loss of reward, as well as to deficits in escape and avoidance learning. We hypothesized that a dopamine signal might underlie the negative reinforcement of avoidance responses and that LHb activation could block this signal and thereby cause avoidance deficits. To test this idea, we implanted stimulating electrodes in either the VTA or LHb of gerbils engaged in two-way active avoidance learning, a task that shows learning-associated dopamine changes and that is acquired faster following LHb lesions. We delivered brief electrical brain stimulation whenever the animal performed a correct response, i.e., when the successful avoidance of foot shock was hypothesized to trigger an intrinsic reward signal. During the acquisition phase, VTA stimulation improved avoidance performance, while LHb stimulation impaired it. VTA stimulation appeared to improve both acquisition and asymptotic performance of the avoidance response, as VTA-stimulated animals reached above-normal performance but reverted to normal responding when stimulation was discontinued. The effects of LHb stimulation during avoidance acquisition were long lasting and persisted even after stimulation was discontinued. However, when given after successful acquisition of avoidance behavior, LHb stimulation had no effect, indicating that LHb stimulation specifically impaired avoidance acquisition without affecting memory retrieval or motivation or ability to perform the avoidance response. These results demonstrate opponent roles of LHb and VTA during acquisition but not during retrieval of avoidance learning.

REM sleep enhancement induced by different procedures improves memory retention in rats

Growing evidence supports the idea that sleep following learning is critically involved in memory formation. Recent studies suggest that information acquired during waking is reactivated and possibly consolidated during subsequent sleep, especially during rapid‐eye movement (REM) or paradoxical sleep (PS). Critical reviews, however, have questioned PS and memory relationships, particularly because of shortcomings of the PS deprivation paradigm applied in many studies. Therefore, in the present study we used an opposite strategy, i.e. we investigated the effects of PS enhancement on memory retention. In three experiments, we found that selective PS enhancement, induced by different procedures after discrimination training in rats, results in increased retention tested 24 h later. Moreover, calculated in all animals (n = 61), there was a highly significant correlation between post‐training PS values and retention scores. Our results suggest that an experimentally induced increase of PS after learning facilitates memory consolidation.

Behavioral and EEG changes in male 5xFAD mice.

Transgenic animal models of Alzheimers disease (AD) are widely used to investigate mechanisms of pathophysiology and cognitive dysfunctions. A model with a very early development of parenchymal plaque load at the age of 2months is the 5xFAD mouse (Tg6799, Oakley et al. 2006). These 5xFAD mice over-express both human amyloid precursor protein (APP) and human presenilin 1 (PS1). Mice from this line have a high APP expression correlating with a high burden and an accelerated accumulation of the 42 amino acid species of amyloid-β (Aβ). The aim of this study was the behavioral and functional investigations of 5xFAD males because in most studies females of this strain were characterized. In comparison to literature of transgenic 5xFAD females, transgenic 5xFAD males showed decreased anxiety in the elevated plus maze, reduced locomotion and exploration in the open field and disturbances in learning performance in the Morris water maze starting at 9months of age. Electroencephalogram (EEG) recordings on 6month old transgenic mice revealed a decrease of delta, theta, alpha, beta and gamma frequency bands whereas the subdelta frequency was increased. EEG recordings during sleep showed a reduction of rapid eye movement sleep in relation to the amount of total sleep. Thus, 5xFAD males develop early functional disturbances and subsequently behavioral deficits and therefore they are a good mouse model for studying Alzheimers disease.

Inhibition of group I metabotropic glutamate receptors blocks spatial learning in rats

Metabotropic glutamate receptors (mGluRs) are postulated to play a role in long-term potentiation and in learning and memory-formation. Previously, we found that the group I/II mGluR antagonist, (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG), blocks Y-maze spatial alternation learning. In this study, we tested the group I mGluR antagonist (S)4-carboxyphenylglycine (4-CPG) in comparison with MCPG using the same behavioural paradigm. Male Wistar rats were intracerebroventricularly injected with either 29 microg 4-CPG or 209 microg MCPG, 30 min prior to learning. Neither 4-CPG nor MCPG had an effect on spatial alternation performance in the training session. In the memory-retention test 24 h later, however, both the 4-CPG- and the MCPG-treated animals were strongly impaired compared with NaCl-injected control rats. These results suggest a particular importance of group I mGluRs in spatial memory-formation and indicate that MCPG effects found in previous learning experiments were predominantly due to an action at group I mGluRs.

The Role of Dopamine in the Context of Aversive Stimuli with Particular Reference to Acoustically Signaled Avoidance Learning

Learning from punishment is a powerful means for behavioral adaptation with high relevance for various mechanisms of self-protection. Several studies have explored the contribution of released dopamine (DA) or responses of DA neurons on reward seeking using rewards such as food, water, and sex. Phasic DA signals evoked by rewards or conditioned reward predictors are well documented, as are modulations of these signals by such parameters as reward magnitude, probability, and deviation of actually occurring from expected rewards. Less attention has been paid to DA neuron firing and DA release in response to aversive stimuli, and the prediction and avoidance of punishment. In this review, we first focus on DA changes in response to aversive stimuli as measured by microdialysis and voltammetry followed by the change in electrophysiological signatures by aversive stimuli and fearful events. We subsequently focus on the role of DA and effect of DA manipulations on signaled avoidance learning, which consists of learning the significance of a warning cue through Pavlovian associations and the execution of an instrumental avoidance response. We present a coherent framework utilizing the data on microdialysis, voltammetry, electrophysiological recording, electrical brain stimulation, and behavioral analysis. We end by outlining current gaps in the literature and proposing future directions aimed at incorporating technical and conceptual progress to understand the involvement of reward circuit on punishment based decisions.