Recurrent activity in higher order, modality non-specific brain regions: a Granger causality analysis of autobiographic memory retrieval

It has been proposed that the workings of the brain are mainly intrinsically generated recurrent neuronal activity, with sensory inputs as modifiers of such activity in both sensory and higher order modality non-specific regions. This is supported by the demonstration of recurrent neuronal activity in the visual system as a response to visual stimulation. In contrast recurrent activity has never been demonstrated before in higher order modality non-specific regions. Using magneto-encephalography and Granger causality analysis, we tested in a paralimbic network the hypothesis that stimulation may enhance causal recurrent interaction between higher-order, modality non-specific regions. The network includes anterior cingulate/medial prefrontal and posterior cingulate/medial parietal cortices together with pulvinar thalami, a network known to be effective in autobiographic memory retrieval and self-awareness. Autobiographic memory retrieval of previous personal judgments of visually presented words was used as stimuli. It is demonstrated that the prestimulus condition is characterized by causal, recurrent oscillations which are maximal in the lower gamma range. When retrieving previous judgments of visually presented adjectives, this activity is dramatically increased during the stimulus task as ascertained by Granger causality analysis. Our results confirm the hypothesis that stimulation may enhance causal interaction between higher order, modality non-specific brain regions, exemplified in a network of autobiographical memory retrieval.     

A noncholinergic action of acetylcholinesterase (AChE) in the brain: From neuronal secretion to the generation of movement

1. In various brain regions, there is a puzzling disparity between large amounts of acetylcholinesterase and low levels of acetylcholine. One such area is the substantia nigra. Furthermore, within the substantia nigra, a soluble form of acetylcholinesterase is released from the dendrites of dopamine-containing nigrostriatal neurons, independent of cholinergic transmission. These two issues have prompted the hypothesis that acetylcholinesterase released in the substantia nigra has an unexpected noncholinergic function. 2. Electrophysiological studies demonstrate that this dendritic release is a function, not of the excitability of the cell from which the acetylcholinesterase is released, but of the inputs to it. In order to explore this phenomenon at the behavioral level, a novel system has been developed for detecting release of acetylcholinesterase "on-line." It can be seen that release of this protein within the substantia nigra can reflect, but is not causal to, movement. 3. Once released, the possible actions of acetylcholinesterase can be studied at both the cellular and the behavioral level. Independent of its catalytic site, acetylcholinesterase has a "modulatory" action on nigrostriatal neurons. The functional consequences of this modulation would be to enhance the sensitivity of the cells to synaptic inputs. 4. Many basic questions remain regarding the release and action of acetylcholinesterase within the substantia nigra and, indeed, within other areas of the brain. Nonetheless, tentative conclusions can be formulated that begin, in a new way, to provide a link between cellular mechanisms and the control of movement.     

Awareness of Memory Deficits in Early Stage Huntington's Disease

Patients with Huntington''s disease (HD) are often described as unaware of their motor symptoms, their behavioral disorders or their cognitive deficits, including memory. Nevertheless, because patients with Parkinson''s disease (PD) remain aware of their memory deficits despite striatal dysfunction, we hypothesize that early stage HD patients in whom degeneration predominates in the striatum can accurately judge their own memory disorders whereas more advanced patients cannot. In order to test our hypothesis, we compared subjective questionnaires of memory deficits (in HD patients and in their proxies) and objective measures of memory dysfunction in patients. Forty-six patients with manifest HD attending the out-patient department of the French National Reference Center for HD and thirty-three proxies were enrolled. We found that HD patients at an early stage of the disease (Stage 1) were more accurate than their proxies at evaluating their own memory deficits, independently from their depression level. The proxies were more influenced by patients'' functional decline rather than by patients'' memory deficits. Patients with moderate disease (Stage 2) misestimated their memory deficits compared to their proxies, whose judgment was nonetheless influenced by the severity of both functional decline and depression. Contrasting subjective memory ratings from the patients and their objective memory performance, we demonstrate that although HD patients are often reported to be unaware of their neurological, cognitive and behavioral symptoms, it is not the case for memory deficits at an early stage. Loss of awareness of memory deficits in HD is associated with the severity of the disease in terms of CAG repeats, functional decline, motor dysfunction and cognitive impairment, including memory deficits and executive dysfunction.     

Protective Effect of Nerolidol Against Pentylenetetrazol-Induced Kindling,Oxidative Stress and Associated Behavioral Comorbidities in Mice

The present study was aimed to investigate the effect of nerolidol on the development of kindling and associate oxidative stress and behavioral comorbidities. Kindling was induced by repeated injections of a sub-convulsive dose of pentylenetetrazol (PTZ-35 mg/kg; i.p.), at an interval of 48?±?2 h for 43 days (21 injections). Nerolidol was administered daily in three doses (12.5, 25 and 50 mg/kg) along with alternate day PTZ injection. To access behavioral comorbidities, animals were subjected to tail suspension test (TST) and passive shock avoidance (PSA) test to evaluate the associated depression and memory impairment respectively on the last day of PTZ administration. Following behavioral assessment, neurotransmitter level and oxidative stress markers were evaluated in brain. The results showed that nerolidol significantly suppressed the progression of kindling. Also, nerolidol ameliorates the kindling associated depression and memory impairment as indicated by decreased immobility time and increased step down latency, respectively, as compared to vehicle control animals. Further, these behavioral observations were complimented with corresponding neurochemical and oxidative stress markers changes. In conclusion, the results of present study showed that nerolidol treatment has protective effect against PTZ-induced kindling and associated oxidative stress and behavioral comorbidities.     

An inexpensive and flexible personal-computer-based system for controlling the multiple stimulus events in classical conditioning]

For the demand of biological discipline it is worth to develop a stimulus control system especially suitable for behavioral studies on learning and memory, in which the precise temporal control of the event sequence has been desired. We developed a flexible and inexpensive system based on IBM-PC for the classical conditioning of the marine mollusc. User can set a various temporal conditions with the data sheet on a display. It can be applicable in a wide range of conditions as well as in a lot of situations which require temporal control of multiple stimuli.     

Bang-bang control of feeding: role of hypothalamic and satiety signals

Rats, people, and many other omnivores eat in meals rather than continuously. We show by experimental test that eating in meals is regulated by a simple bang-bang control system, an idea foreshadowed by Le Magnen and many others, shown by us to account for a wide range of behavioral data, but never explicitly tested or tied to neurophysiological facts. The hypothesis is simply that the tendency to eat rises with time at a rate determined by satiety signals. When these signals fall below a set point, eating begins, in on–off fashion. The delayed sequelae of eating increment the satiety signals, which eventually turn eating off. Thus, under free conditions, the organism eats in bouts separated by noneating activities. We report an experiment with rats to test novel predictions about meal patterns that are not explained by existing homeostatic approaches. Access to food was systematically but unpredictably interrupted just as the animal tried to start a new meal. A simple bang-bang model fits the resulting meal-pattern data well, and its elements can be identified with neurophysiological processes. Hypothalamic inputs can provide the set point for longer-term regulation carried out by a comparator in the hindbrain. Delayed gustatory and gastrointestinal aftereffects of eating act via the nucleus of the solitary tract and other hindbrain regions as neural feedback governing short-term regulation. In this way, the model forges real links between a functioning feedback mechanism, neuro–hormonal data, and both short-term (meals) and long-term (eating-rate regulation) behavioral data.     

Cognitive Behavioral Performance of Untreated Depressed Patients with Mild Depressive Symptoms

This study evaluated the working memory performance of 18 patients experiencing their first onset of mild depression without treatment and 18 healthy matched controls. The results demonstrated that working memory impairment in patients with mild depression occurred when memorizing the position of a picture but not when memorizing the pictures themselves. There was no significant difference between the two groups in the emotional impact on the working memory, indicating that the attenuation of spatial working memory was not affected by negative emotion; however, cognitive control selectively affected spatial working memory. In addition, the accuracy of spatial working memory in the depressed patients was not significantly reduced, but the reaction time was significantly extended compared with the healthy controls. This finding indicated that there was no damage to memory encoding and function maintenance in the patients but rather only impaired memory retrieval, suggesting that the extent of damage to the working memory system and cognitive control abilities was associated with the corresponding depressive symptoms. The development of mild to severe depressive symptoms may be accompanied by spatial working memory damage from the impaired memory retrieval function extending to memory encoding and memory retention impairments. In addition, the impaired cognitive control began with an inadequate capacity to automatically process internal negative emotions and further extended to impairment of the ability to regulate and suppress external emotions. The results of the mood-congruent study showed that the memory of patients with mild symptoms of depression was associated with a mood-congruent memory effect, demonstrating that mood-congruent memory was a typical feature of depression, regardless of the severity of depression. This study provided important information for understanding the development of cognitive dysfunction.     

A Cognitive Neural Architecture Able to Learn and Communicate through Natural Language

Communicative interactions involve a kind of procedural knowledge that is used by the human brain for processing verbal and nonverbal inputs and for language production. Although considerable work has been done on modeling human language abilities, it has been difficult to bring them together to a comprehensive tabula rasa system compatible with current knowledge of how verbal information is processed in the brain. This work presents a cognitive system, entirely based on a large-scale neural architecture, which was developed to shed light on the procedural knowledge involved in language elaboration. The main component of this system is the central executive, which is a supervising system that coordinates the other components of the working memory. In our model, the central executive is a neural network that takes as input the neural activation states of the short-term memory and yields as output mental actions, which control the flow of information among the working memory components through neural gating mechanisms. The proposed system is capable of learning to communicate through natural language starting from tabula rasa, without any a priori knowledge of the structure of phrases, meaning of words, role of the different classes of words, only by interacting with a human through a text-based interface, using an open-ended incremental learning process. It is able to learn nouns, verbs, adjectives, pronouns and other word classes, and to use them in expressive language. The model was validated on a corpus of 1587 input sentences, based on literature on early language assessment, at the level of about 4-years old child, and produced 521 output sentences, expressing a broad range of language processing functionalities.     

The Strategies of Behavioral Control in a Coelenterate

Although the cellular substrates of behavioral coordinationare uncertain in the hydroid Tubularia, much is known aboutthe strategies of behavioral control. The picture which emergesis that of an animal with diffusely distributed sites capableof initiating spontaneous activity, regional coordination ofpotential pacemaker loci to form pacemaker systems, and a loosehierarchical organization of pacemaker systems. At least onepacemaker system shows a short term increase in excitabilityand a longer duration depression of excitability following firing.The short-term excitability increase gives a tendency to firein bursts, the long-term depression acts as an intrinsic inhibitoryfeedback to terminate bursts and to control output frequency.All the known interactions between pacemaker systems are excitatory.Exogenous stimuli can excite a conducting system which inhibitsmost of the pacemaker systems, and one pacemaker system specificallyinhibits one set of muscles.     

Possible mechanisms for forming typological features of behavior of WAG/Rij line rats

Typological behavior reactions of WAG/Rij rats were studied from the standpoint of divergent modulatory integration hypothesis. This rat strain has a genetically determined dominant dysfunction of the benzodiazepine system of the thalamic nuclei. This disorder provokes an epileptiform disease such as absence epilepsy. It was suggested that the dysfunction of this system would result in a modification of the modulatory systems, which support the motivation states of escape and avoidance reactions as well as of the modulatory systems, which form the emotional states. Modifications of these states are the background of typological behavioral features of WAG/Rij rats. It was shown that WAG/Rij have the lower threshold of the development of haloperidol catalepsy, higher levels of fear and depression. On the first day of training in a shuttle box, WAG/Rij rats demonstrated better avoidance performance than Wistar rats. On the second and 28th days, the amnestic effect of the epileptiform disease was observed. The amnestic effect was also observed after passive avoidance conditioning. The results are discussed in terms of the modulatory integratin hypothesis.     

Within-session dynamics of theta–gamma coupling and high-frequency oscillations during spatial alternation in rat hippocampal area CA1

Theta–gamma coupling in the hippocampus is thought to be involved in cognitive processes. A large body of research establishes that the hippocampus plays a crucial role in the organization and maintenance of episodic memory, and that sharp-wave ripples (SWR) contribute to memory consolidation processes. Here, we investigated how the local field potentials in the hippocampal CA1 area adapted along with rats’ behavioral changes within a session during a spatial alternation task that included a 1-s fixation and a 1.5-s delay. We observed that, as the session progressed, the duration from fixation onset to nose-poking in the choice hole reduced as well as the number of premature responses during the delay. Parallel with the behavioral transitions, the power of high gamma during the delay period increased whereas that of low gamma decreased later in the session. Furthermore, the strength of theta–gamma modulation later in the session showed significant increase as compared to earlier in the session. Examining SWR during the reward period, we found that the number of SWR events decreased as well as the power in a wide frequency range during SWR events. In addition, the correlation between SWR and gamma oscillations just before SWR events was higher in the earlier trials than in the later trials. Our findings support the notion that the inputs from CA3 and entorhinal cortex play a critical role in memory consolidation as well as in cognitive processes. We suggest that SWR and the inputs from the two areas serve to stabilize the task behavior and neural activities.     

No correlation between inbreeding depression and delayed selfing in the freshwater snail Physa acuta

Inbreeding depression, one of the main factors driving mating system evolution, can itself evolve as a function of the mating system (the genetic purging hypothesis). Classical models of coevolution between mating system and inbreeding depression predict negative associations between inbreeding depression and selfing rate, but more recent approaches suggest that negative correlations should usually be too weak or transient to be detected within populations. Empirical results remain unclear and restricted to plants. Here, we evaluate, for the first time, the within-population genetic correlation between inbreeding depression and a trait that controls the amount of self-fertilization (the waiting time) in a self-fertile hermaphroditic animal, the freshwater snail Physa acuta. Using a large quantitative-genetic design (36 grand-families and 348 families), we observe abundant within-population family-level genetic variation for both inbreeding depression (estimated for survival, fecundity, and size) and the degree of behavioral selfing avoidance. However, we detected no correlation between waiting time and inbreeding depression across families. In agreement with recent models, this result shows that mutational variance rather than differential purging accounts for most of the genetic variance in inbreeding depression within a population.     

Effects of air ions on some aspects of learning and memory of rats and mice

When submitted to a single avoidance task male mice showed different behavioral responses if previously treated with opposite aeroionization polarities. Whereas negative air ions tend to improve learning, positive ions have disturbing effects. Male rats submitted to a single — trial inhibitory avoidance step-through task showed that retention processes may also be influenced by air ions. The positive air-ion-treated animals exhibit signs of impaired short and long term memory. The slightly impaired score of negative air-ion-treated animals seems only dependent upon the simultaneously increased locomotor activity. A separate experiment supported this hypothesis showing conspicuous differential effects of air ion polarity on spontaneous activity of male rats. On the basis of these findings and the results of other studies in biological air ion dependence field, the behavioral significance of aero-ionization in learning and memory processes is discussed in relation to serotonin metabolism and other neuroendocrine mechanisms.     

Changes in the Properties of Glutamatergic Synapses in the Medial Prefrontal Cortex and Nucl. Accumbens in Rats with Behavioral Depression

In experiments on surviving rat forebrain slices, we studied the characteristics of glutamatergic synaptic transmission in the medial prefrontal cortex (MPFC) and nucl. accumbens. It was found that in rats with behavioral depression induced by zoosocial isolation (72 h), the mean amplitude of field EPSP (fEPSP) in the MPFC demonstrated no significant alterations. At the same time, the developments of rhythmic stimulation-caused long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission were suppressed, as compared with the control. In the nucl. accumbens of rats with behavioral depression, the mean fEPSP amplitude increased by nearly 25%, whereas rhythmic stimulation-induced LTD of transmission through synaptic connections between the cortex and nucl. accumbens weakened. Changes in the relay and plastic properties of glutamatergic synapses typical of behavioral depression were reproduced under conditions of chronic (for 3 days) i.p. injections of 1 mg/kg dexamethasone into the experimental animals. The influences exerted on brain slices in vitro by a synthetic glucocorticoid, dexamethasone, and a mineralocorticoid, deoxycorticosterone acetate, applied over 2 h in concentrations of 100 nM, did not significantly affect glutamatergic synaptic transmission in the MPFC and nucl. accumbens. In brain slices from animals with behavioral depression or from those subjected to chronic injection of dexamethasone, we observed a reduction of the modulatory effect of dexamethasone and a nonselective agonist of dopamine receptors, apomorphine hydrochloride, on glutamatergic synaptic transmission in the MPFC and nucl. accumbens. This is considered an indirect reflection of a decrease in the efficiency (down-regulation) of glucocorticoid and dopamine receptors in neurons of the brain structures under study. It is hypothesized that changes in the main properties of glutamatergic synapses in the forebrain structures (MPFC and nucl. accumbens), which were observed under conditions of behavioral depression, are determined by both direct effects of glucocorticoids on cortical and mesolimbic neurons and indirect effects mediated by the cerebral dopaminergic system.     

Evaluation of cognitive function of fluoxetine, sertraline and tianeptine in isolation and chronic unpredictable mild stress-induced depressive Wistar rats

Depressive illness is generally associated with cognitive impairment. Serotonergic selective antidepressant drugs, fluoxetine (FLX), sertraline (SER) and tianeptine (TIA), are claimed to have less or no effect on cholinergic system, the key system involved in memory. In the present study, these drugs were evaluated for their influence on cognitive behavior in both depressive and non-depressive animals. Depression was induced by two models, (i) 60 days social isolation of litter; and ii) by applying chronic unpredictable mild stress for 21 days. Depression in the rats was confirmed by behavioral despair test. Transfer latency on elevated plus maze and inflexion ratio in passive avoidance step through behavior were employed to assess learning and memory. The results indicated that administration of fluoxetine; sertraline and tianeptine attenuated the cognitive deficits observed in depressive rats. In non-depressive rats these drugs produced retention deficit, which was found to be parameter and model dependent. Data suggested that, FLX and SER (SSRI's) effectively attenuated the isolation-induced depression and cognitive deficit, whereas TIA (SSRE) produced better effect in stress-induced depressive conditions. It was concluded that behavioral profiles of fluoxetine, sertraline and tianeptine on cognition were model and parameter dependent.     

Interval timing in genetically modified mice: a simple paradigm

We describe a behavioral screen for the quantitative study of interval timing and interval memory in mice. Mice learn to switch from a short-latency feeding station to a long-latency station when the short latency has passed without a feeding. The psychometric function is the cumulative distribution of switch latencies. Its median measures timing accuracy and its interquartile interval measures timing precision. Next, using this behavioral paradigm, we have examined mice with a gene knockout of the receptor for gastrin-releasing peptide that show enhanced (i.e. prolonged) freezing in fear conditioning. We have tested the hypothesis that the mutants freeze longer because they are more uncertain than wild types about when to expect the electric shock. The knockouts however show normal accuracy and precision in timing, so we have rejected this alternative hypothesis. Last, we conduct the pharmacological validation of our behavioral screen using d -amphetamine and methamphetamine. We suggest including the analysis of interval timing and temporal memory in tests of genetically modified mice for learning and memory and argue that our paradigm allows this to be done simply and efficiently.     

Timing actions to avoid refractoriness: a simple solution for streaming sensory signals

Segmenting self- from allo-generated signals is crucial for active sensory processing. We report a dynamic filter used by South American pulse electric fish to distinguish active electro-sensory signals carried by their own electric discharges from other concomitant electrical stimuli (i.e. communication signals). The filter has a sensory component, consisting of an onset type central electro-sensory neuron, and a motor component, consisting of a change in the fish's discharge rate when allo-generated electrical events occur in temporal proximity to the fish's own discharge. We investigated the sensory component of the filter by in vitro mimicking synaptic inputs occurring during behavioral responses to allo-generated interfering signals. We found that active control of the discharge enhances self-generated over allo-generated responses by forcing allo-generated signals into a central refractory period. This hypothesis was confirmed by field potential recordings in freely discharging fish. Similar sensory-motor mechanisms may also contribute to signal segmentation in other sensory systems.     

Hippocampus-dependent retrieval and hippocampus-independent extinction of place avoidance navigation,and stress-induced out-of-context activation of a memory revealed by reversible lesion experiments in rats

The use of reversible lesion techniques in memory research was pioneered in the laboratory of Jan Bures and Olga Buresova. We use the occasion of Jan's 75th birthday to briefly review the experimental utility of this approach. Two experiments from our current research are reported in which reversible lesioning methods are used to ask otherwise experimentally untenable questions about memory retrieval. The first experiment used intra-hippocampal injections of tetrodotoxin to temporarily inactivate the hippocampus during retrieval of a well-learned place avoidance navigation memory. This revealed that the hippocampus is necessary for place avoidance retrieval but that the extinction of place avoidance can occur independently of retrieving the memory and intact hippocampal function. The second experiment used KCl-induced cortical spreading depression in an interhippocampal transfer paradigm to demonstrate that a Y-maze memory that is learned by only one cortical hemisphere can be made to transfer to the other hemisphere by forcing the rat to swim, a unique stressful experience that occurred in a different apparatus, different behavioral context, and involved different behaviors than the Y-maze training. This demonstrates, we believe for the first time behaviorally, that memories can be activated outside of the behavioral context of their acquisition and expression in rats.