Memory formation and retrieval of neuronal silencing in the auditory cortex.

Sensory stimuli not only activate specific populations of cortical neurons but can also silence other populations. However, it remains unclear whether neuronal silencing per se leads to memory formation and behavioral expression. Here we show that mice can report optogenetic inactivation of auditory neuron ensembles by exhibiting fear responses or seeking a reward. Mice receiving pairings of footshock and silencing of a neuronal ensemble exhibited a fear response selectively to the subsequent silencing of the same ensemble. The valence of the neuronal silencing was preserved for at least 30 d and was susceptible to extinction training. When we silenced an ensemble in one side of auditory cortex for conditioning, silencing of an ensemble in another side induced no fear response. We also found that mice can find a reward based on the presence or absence of the silencing. Neuronal silencing was stored as working memory. Taken together, we propose that neuronal silencing without explicit activation in the cerebral cortex is enough to elicit a cognitive behavior.

Mushroom body output neurons encode valence and guide memory-based action selection in Drosophila.

Animals discriminate stimuli, learn their predictive value and use this knowledge to modify their behavior. In Drosophila, the mushroom body (MB) plays a key role in these processes. Sensory stimuli are sparsely represented by ∼2000 Kenyon cells, which converge onto 34 output neurons (MBONs) of 21 types. We studied the role of MBONs in several associative learning tasks and in sleep regulation, revealing the extent to which information flow is segregated into distinct channels and suggesting possible roles for the multi-layered MBON network. We also show that optogenetic activation of MBONs can, depending on cell type, induce repulsion or attraction in flies. The behavioral effects of MBON perturbation are combinatorial, suggesting that the MBON ensemble collectively represents valence. We propose that local, stimulus-specific dopaminergic modulation selectively alters the balance within the MBON network for those stimuli. Our results suggest that valence encoded by the MBON ensemble biases memory-based action selection.

Effect of Electromagnetic Pulses (EMP) on associative learning in mice and a preliminary study of mechanism.

PURPOSE: To investigate the effects of electromagnetic pulses (EMP) on associative learning in mice and test a preliminary mechanism for these effects. MATERIALS AND METHODS: A tapered parallel plate gigahertz transverse electromagnetic (GTEM) cell with a flared rectangular coaxial transmission line was used to expose male BALB/c mice to EMP (peak-intensity 400 kV/m, rise-time 10 ns, pulse-width 350 ns, 0.5 Hz and total 200 pulses). Concurrent sham-exposed mice were used as a control. Associative learning, oxidative stress in the brain, serum chemistry and the protective action of tocopherol monoglucoside (TMG) in mice were measured, respectively. RESULTS: (1) Twelve hour and 1 day post EMP exposure associative learning was reduced significantly compared with sham control (p<0.05) but recovered at 2 d post EMP exposure. (2) Compared with the sham control, lipid peroxidation of brain tissue and chemiluminescence (CL) intensity increased significantly (p<0.05), while the activity of the antioxidant enzymes Superoxide Dismutase [SOD], Glutathione [GSH], Glutathione Peroxidase [GSH-Px], Catalase [CAT]) decreased significantly (p<0.05) at 3 h, 6 h, 12 h and 1 d post EMP exposure. All these parameters recovered at 2 d post EMP exposure. (3) No significant differences between the sham control group and EMP exposed group were observed in serum cholesterol and triglycerides. (4) Pretreatment of mice with TMG showed protective effects to EMP exposure. CONCLUSIONS: EMP exposure significantly decreased associative learning in mice and TMG acted as an effective protective agent from EMP exposure. This mechanism could involve an increase of oxidative stress in brain by EMP exposure.

Frontal and parietal contributions to probabilistic association learning.

Neuroimaging studies have shown both dorsolateral prefrontal (DLPFC) and inferior parietal cortex (iPARC) activation during probabilistic association learning. Whether these cortical brain regions are necessary for probabilistic association learning is presently unknown. Participants' ability to acquire probabilistic associations was assessed during disruptive 1 Hz repetitive transcranial magnetic stimulation (rTMS) of the left DLPFC, left iPARC, and sham using a crossover single-blind design. On subsequent sessions, performance improved relative to baseline except during DLPFC rTMS that disrupted the early acquisition beneficial effect of prior exposure. A second experiment examining rTMS effects on task-naive participants showed that neither DLPFC rTMS nor sham influenced naive acquisition of probabilistic associations. A third experiment examining consecutive administration of the probabilistic association learning test revealed early trial interference from previous exposure to different probability schedules. These experiments, showing disrupted acquisition of probabilistic associations by rTMS only during subsequent sessions with an intervening night's sleep, suggest that the DLPFC may facilitate early access to learned strategies or prior task-related memories via consolidation. Although neuroimaging studies implicate DLPFC and iPARC in probabilistic association learning, the present findings suggest that early acquisition of the probabilistic cue-outcome associations in task-naive participants is not dependent on either region.

A magnetic field effect on learning in male golden hamsters.

The aim of this experiment was to investigate the influence of repeated exposure to 10, 20, 30 or 40 Hz magnetic fields at 0.1T on the learning of male golden hamsters in a Skinner box, in which the animals learned to press a lever to receive a food reward. The latency of the first response was not affected by exposure to the magnetic fields used in this experiment. No significant field-dependent effects on the performance of the task were observed in males exposed to 10 and 20 Hz magnetic fields at 0.1T. However, exposure significantly improved the learning of the task in animals exposed to 30 and 40 Hz magnetic fields at 0.1T.

Priming, response learning and repetition suppression.

Prior exposure to a stimulus can facilitate its subsequent identification and classification, a phenomenon called priming. This behavioural facilitation is usually accompanied by a reduction in neural response within specific cortical regions (repetition suppression, RS). Recent research has suggested that both behavioural priming and RS can be largely determined by previously learned stimulus-response associations. According to this view, a direct association forms between the stimulus presented and the response made to it. On a subsequent encounter with the stimulus, this association automatically cues the response, bypassing the various processing stages that were required to select that response during its first presentation. Here we reproduce behavioural evidence for such stimulus-response associations, and show the PFC to be sensitive to such changes. In contrast, RS within ventral temporal regions (such as the fusiform cortex), which are usually associated with perceptual processing, is shown to be robust to response changes. The present study therefore suggests a dissociation between RS within the PFC, which may be sensitive to retrieval of stimulus-response associations, and RS within posterior perceptual regions, which may reflect facilitation of perceptual processing independent of stimulus-response associations.

Modulatory effect of ionizing radiation on food-NaCl associative learning: the role of gamma subunit of G protein in Caenorhabditis elegans.

Ionizing radiation (IR) is known to impair learning by suppressing adult neurogenesis in the hippocampus. However, in a mature nervous system, IR-induced functional alterations that are independent of neurogenesis remain largely unknown. In the present study, we analyzed the effects of IR on a food-NaCl associative learning paradigm of adult Caenorhabditis elegans that does not undergo neurogenesis. We observed that a decrease in chemotaxis toward NaCl occurs only after combined starvation and exposure to NaCl. Exposure to IR induced an additional decrease in chemotaxis immediately after an acute dose in the transition stage of the food-NaCl associative learning. Strikingly, chronic irradiation induced negative chemotaxis in the exposed animals, i.e., the primary avoidance response. IR-induced additional decreases in chemotaxis after acute and chronic irradiation were significantly suppressed in the gpc-1 mutant, which was defective in GPC-1 (one of the two gamma subunits of the heterotrimeric G-protein). Chemotaxis to cAMP, but not to lysine and benzaldehyde, was influenced by IR during the food-NaCl associative learning. Our novel findings suggest that IR behaves as a modulator in the food-NaCl associative learning via C. elegans GPC-1 and a specific neuronal network and may shed light on the modulatory effect of IR on learning.

Rats avoid high magnetic fields: dependence on an intact vestibular system.

High strength static magnetic fields are thought to be benign and largely undetectable by mammals. As magnetic resonance imaging (MRI) machines increase in strength, however, potential aversive effects may become clinically relevant. Here we report that rats find entry into a 14.1 T magnet aversive, and that they can detect and avoid entry into the magnet at a point where the magnetic field is 2 T or lower. Rats were trained to climb a ladder through the bore of a 14.1 T superconducting magnet. After their first climb into 14.1 T, most rats refused to re-enter the magnet or climb past the 2 T field line. This result was confirmed in a resistive magnet in which the magnetic field was varied from 1 to 14 T. Detection and avoidance required the vestibular apparatus of the inner ear, because labyrinthectomized rats readily traversed the magnet. The inner ear is a novel site for magnetic field transduction in mammals, but perturbation of the vestibular apparatus would be consistent with human reports of vertigo and nausea around high strength MRI machines.

Blocking memory reconsolidation reverses memory-associated changes in glutamate receptor expression.

It has been reported that consolidated memories can return to a labile state when reactivated and undergo a process of re-storage, termed reconsolidation, required for later recall. We investigated memory for a nonassociative learning task (habituation) and found that memory for this task also undergoes reconsolidation after recall. To investigate reconsolidation, we first demonstrated that adult Caenorhabditis elegans are capable of reliable memory 48 h after habituation training (p < 0.05). When heat shock was administered immediately after a reminder, response magnitudes of trained animals matched response levels of untrained animals: the inhibitory effects of heat shock on protein synthesis disrupted memory reconsolidation. Pharmacological blockade of non-NMDA-type glutamate receptors during reminder also eliminated 48 h retention. When expression levels of a specific glutamate receptor subunit (GLR-1) (40% homology to mammalian AMPA-type glutamate receptors) (Hart et al., 1995; Maricq et al., 1995) were measured 48 h after training, there was a significant decrease in trained compared with untrained controls. If trained worms were given a reminder followed immediately by heat shock, the effect of training on GLR-1 levels was reversed. From these studies, we conclude that both the behavioral expression of long-term memory for habituation and a cellular correlate of that memory (the alteration in expression levels of GLR-1) in C. elegans can be altered after retrieval. Furthermore, conditions that impair memory consolidation similarly disrupt memory reconsolidation, suggesting that similar mechanisms are involved.

The role of the right dorsal premotor cortex in visuomotor learning: a transcranial magnetic stimulation study.

To study the role of the right dorsal premotor cortex in visuomotor association learning (association of four visual stimuli to four buttons), transcranial magnetic stimulation was applied to this area to interfere with the ongoing learning processes. Two transcranial magnetic stimulation pulses to the right dorsal premotor cortex at 150 and 200 ms after onset of the imperative stimulus resulted in the abolishing of reaction time decreases during learning. Transcranial magnetic stimulation applied to a control region revealed no influence on reaction time decreases. During both conditions, however, there were similar increases of accuracy scores. We conclude that the right dorsal premotor cortex is not directly involved in associating visual with motor cues. We suggest that this area is intimately involved in selection and preparation of forthcoming movements.

Context-dependent olfactory learning in an insect.

We studied the capability of the cricket Gryllus bimaculatus to select one of a pair of odors and to avoid the other in one context and to do the opposite in another context. One group of crickets was trained to associate one of a pair of odors (conditioned stimulus, CS1) with water reward (appetitive unconditioned stimulus, US+) and another odor (CS2) with saline solution (aversive US, US-) under illumination and to associate CS1 with US- and CS2 with US+ in the dark. Another group of crickets received training of the opposite stimulus arrangement. At 1 d after the training for 3 d, the former group significantly preferred CS1 over CS2 under illumination but preferred CS2 over CS1 in the dark, and the latter group exhibited the opposite odor preference. The results of control experiments showed that the background light condition had no significant effects on memory formation or retrieval unless it was explicitly associated with US during training. Thus, the visual context affected learning performance only when crickets were requested to use it to disambiguate the meaning of CSs and to predict USs.

Failure to produce taste-aversion learning in rats exposed to static electric fields and air ions.

Taste-aversion (TA) learning was measured to determine whether exposure to high-voltage direct current (HVdc) static electric fields can produce TA learning in male Long Evans rats. Fifty-six rats were randomly distributed into four groups of 14 rats each. All rats were placed on a 20 min/day drinking schedule for 12 consecutive days prior to receiving five conditioning trials. During the conditioning trials, access to 0.1% sodium saccharin-flavored water was given for 20 min, followed 30 min later by one of four treatments. Two groups of 14 rats each were individually exposed to static electric fields and air ions, one group to +75 kV/m (+2 x 10(5) air ions/cm3) and the other group to -75 kV/m (-2 x 10(5) air ions/cm3). Two other groups of 14 rats each served as sham-exposed controls, with the following variation in one of the sham-exposed groups: This group was subdivided into two subsets of seven rats each, so that a positive control group could be included to validate the experimental design. The positive control group (n = 7) was injected with cyclophosphamide 25 mg/kg, i.p., 30 min after access to saccharin-flavored water on conditioning days, whereas the other subset of seven rats was similarly injected with an equivalent volume of saline. Access to saccharin-flavored water on conditioning days was followed by the treatments described above and was alternated daily with water "recovery" sessions in which the rats received access to water for 20 min in the home cage without further treatment. Following the last water-recovery session, a 20 min, two-bottle preference test (between water and saccharin-flavored water) was administered to each group. The positive control group did show TA learning, thus validating the experimental protocol. No saccharin-flavored water was consumed in the two-bottle preference test by the cyclophosphamide-injected, sham-exposed group compared to 74% consumed by the saline-injected sham-exposed controls (P < .0001). Saccharin-preference data for the static field-exposed groups showed no TA learning compared to data for sham-exposed controls. In summary, exposure to intense static electric fields and air ions did not produce TA learning as assessed by this particular design.

Brain tumors in children and adolescents--III. Effects of radiation and hormone status on intelligence and on working, associative and serial-order memory.

The effects on intelligence and memory of two post-surgical conditions (radiation treatment, hormone deficiency and supplementation) were explored in 46 children and adolescents with tumors in a variety of brain sites. Verbal intelligence, but not non-verbal intelligence, varied positively with age at radiation treatment. Memory for word meanings was unrelated to either radiation history or to hormone status. Severe deficits in serial position memory occurred with impaired hormone function and an older age at tumor onset. Severe deficits in working memory were associated with a history of radiation and a principal tumor site that involved thalamic/epithalamic brain regions. Radiation treatment and hormone status affect later cognitive function in children and adolescents with brain tumors. Although the greater vulnerability of the verbal intelligence of the younger radiated child and the serial order memory of the child with later tumor onset and hormone disturbances remain to be explained, and although the form of the relationship between radiation and tumor site is not fully understood, the data highlight the need to consider the cognitive consequences of pediatric brain tumors according to a set of markers that include maturational rate, hormone status, radiation history, and principal site of the tumor.