Sleep as a window to target traumatic memories.

Post-traumatic stress disorder (PTSD) is a severe psychiatric disorder in which traumatic memories result in flashbacks and nightmares. With one-third of patients not responding to standard exposure-based psychotherapy, new treatment strategies are needed. Sleep offers a unique time window to enhance therapeutic efficacy. Traumatic memories that are neutralized in therapy need to be stored back into memory (consolidated) during sleep to solidify the treatment effect. New basic research shows that memory consolidation can be enhanced by presenting sounds or scents that were linked to the memory at encoding, again during sleep. This procedure, termed targeted memory reactivation (TMR), has, despite its clinical potential, not been tested in (PTSD) patients. In this narrative review, we explore the potential of TMR as a new sleep-based treatment for PTSD. First we provide the necessary background on the memory and sleep principles underlying PTSD as well as the present applications and conditional factors of TMR. Then, we will discuss the outstanding questions and most promising experimental avenues when testing TMR to treat traumatic memories.

Sleep Fosters Insight Into Real-Life Problems.

Anecdotal reports recount of individuals obtaining insights during sleep. For instance, various acclaimed scientists have attributed some of their greatest insights to sleep-related mentation. To date, this phenomenon has not been systematically investigated. The current study explored the occurrence and characteristics of Sleep-Related Insights (SRIs) in a large population sample, using a questionnaire approach. We found that a large majority of participants (~80%) experienced SRIs at some point in their lives and about 40% obtained SRIs regularly. Most of these subjects could link SRIs to remembered sleep mentation. SRIs were reported to occur in both sleep and half-sleep states, and at any point of the sleep period. Furthermore, SRIs regarded emotional preoccupations about twice as often as theoretical problems. Finally, SRIs were not robustly related to subjective sleep-quality, but small positive correlations with insomnia and narcolepsy-like symptoms were observed. In conclusion, SRIs are much more common than might have been expected, manifest in several forms and appear to be part of normal, healthy sleep. Importantly, the strong link of SRIs with sleep mentation suggests they result from some form of higher-order information processing during sleep, rather than being (fully) secondary to general restorative effects of sleep. Finally, our findings show that a large portion of the sampled population is aware of sleep's benefits for real life problem solving and experiences such benefits on a regular basis.

Mental Schemas Hamper Memory Storage of Goal-Irrelevant Information.

UNLABELLED: Mental schemas exert top-down control on information processing, for instance by facilitating the storage of schema-related information. However, given capacity-limits and competition in neural network processing, schemas may additionally exert their effects by suppressing information with low momentary relevance. In particular, when existing schemas suffice to guide goal-directed behavior, this may actually reduce encoding of the redundant sensory input, in favor of gaining efficiency in task performance. The present experiment set out to test this schema-induced shallow encoding hypothesis. Our approach involved a memory task in which faces had to be coupled to homes. For half of the faces the responses could be guided by a pre-learned schema, for the other half of the faces such a schema was not available. Memory storage was compared between schema-congruent and schema-incongruent items. To characterize putative schema effects, memory was assessed both with regard to visual details and contextual aspects of each item. The depth of encoding was also assessed through an objective neural measure: the parietal old/new ERP effect. This ERP effect, observed between 500-800 ms post-stimulus onset, is thought to reflect the extent of recollection: the retrieval of a vivid memory, including various contextual details from the learning episode. We found that schema-congruency induced substantial impairments in item memory and even larger ones in context memory. Furthermore, the parietal old/new ERP effect indicated higher recollection for the schema-incongruent than the schema-congruent memories. The combined findings indicate that, when goals can be achieved using existing schemas, this can hinder the in-depth processing of novel input, impairing the formation of perceptually detailed and contextually rich memory traces. Taking into account both current and previous findings, we suggest that schemas can both positively and negatively bias the processing of sensory input. An important determinant in this matter is likely related to momentary goals, such that mental schemas facilitate memory processing of goal-relevant input, but suppress processing of goal-irrelevant information. HIGHLIGHTS: - Schema-congruent information suffers from shallow encoding.- Schema congruency induces poor item and context memory.- The parietal old/new effect is less pronounced for schema-congruent items.- Schemas exert different influences on memory formation depending on current goals.

Mode shifting between storage and recall based on novelty detection in oscillating hippocampal circuits.

It has been suggested that hippocampal mode shifting between a storage and a retrieval state might be under the control of acetylcholine (ACh) levels, as set by an autoregulatory hippocampo-septo-hippocampal loop. The present study investigates how such a mechanism might operate in a large-scale connectionist model of this circuitry that takes into account the major hippocampal subdivisions, oscillatory population dynamics and the time scale on which ACh exerts its effects in the hippocampus. The model assumes that hippocampal mode shifting is regulated by a novelty signal generated in the hippocampus. The simulations suggest that this signal originates in the dentate. Novel patterns presented to this structure lead to brief periods of depressed firing in the hippocampal circuitry. During these periods, an inhibitory influence of the hippocampus on the septum is lifted, leading to increased firing of cholinergic neurons. The resulting increase in ACh release in the hippocampus produces network dynamics that favor learning over retrieval. Resumption of activity in the hippocampus leads to the reinstatement of inhibition. Despite theta-locked rhythmic firing of ACh neurons in the septum, ACh modulation in the model fluctuates smoothly on a time scale of seconds. It is shown that this is compatible with the time scale on which memory processes take place. A number of strong predictions regarding memory function are derived from the model.

Interruptions of early cortical development affect limbic association areas and social behaviour in rats; possible relevance for neurodevelopmental disorders.

Deficits in social behaviour are found in several neuropsychiatric disorders with a presumed developmental origin. Adequate social behaviour may rely importantly on the associative integration of new stimuli with previously stored, related information. The limbic allocortex, in particular the entorhinal region, is thought to support this kind of processing. Therefore, in the present study, gestating dams were treated with methylazoxymethanol acetate (MAM) on one of gestational days nine to twelve, to interrupt neuronal proliferation in the entorhinal region of the developing foetuses. Effects of prenatal MAM administration on social behaviour were evaluated in adult animals. As the entorhinal cortex has been implicated by some studies in spatial memory, effects on this function were also investigated. Following the behavioural studies, brain morphology was screened for effects of MAM. Our results show moderate to severe social impairment in MAM-treated animals, depending on the exact timing of prenatal exposure. By contrast, spatial reference and working memory were not importantly affected in any group. Analysis of brain morphology in the MAM-treated offspring supported maldevelopment of the entorhinal cortex and revealed mild abnormalities also in some connected limbic and limbic affiliated structures, such as the perirhinal and ectorhinal cortex, the anterior cingulate cortex and the medial septum-diagonal band region. Findings are discussed with respect to entorhinal cortex function, and with regard to their relevance for psychiatric disorders with a putatively neurodevelopmental pathogenesis, such as schizophrenia.

Acoustic startle responses of rats with cerebral developmental abnormalities: implications for schizophrenia.

Mounting evidence suggests involvement of prenatal factors in the pathogenesis of schizophrenia. The objective of the present study was to provide evidence for the hypothesis on schizophrenia that abnormal fetal brain development leads to impaired sensorimotor gating of acoustic startle stimuli. To this purpose, pregnant rats were treated with methylazoxymethanol acetate on one of four subsequent days of gestation, from E9 to E12. These procedures inhibit early stages of cortical proliferation in the foetuses, resulting in adult brain abnormalities that were mainly found in the entorhinal region. At the adult age, habituation andprepulse inhibition (PPI) of startle responses to acoustic stimuli were investigated. Our results show impaired habituation and PPI in rats treated at embryonic days 10 and 11. It is concluded that sensorimotor gating deficits can result from a developmental abnormality involving the entorhinal region, supporting the hypothesis that similar deficits, often observed in schizophrenic subjects, may be the result of entorhinal cortex dysfunction.

Methylazoxymethanol acetate-induced abnormalities in the entorhinal cortex of the rat; parallels with morphological findings in schizophrenia.

It has been suggested repeatedly that the non-heritable factors in the pathogenesis of schizophrenia involve abnormalities of prenatal neurodevelopment. Furthermore, post-mortem studies show neuropathology of apparently developmental origin in the entorhinal cortex and other brain regions of schizophrenic subjects. In an attempt to model a developmental defect of the entorhinal region in the rat, cerebrocortical proliferation was briefly interrupted during its earliest stages, when the entorhinal area is thought to undergo major cell division. Specifically, the experimental set-up involved the administration of methylazoxymethanol acetate (MAM) on 1 of 4 consecutive days of embryonal development, from E9 to E12. Analysis of the forebrain in adult animals shows reduction of the entorhinal cortex in rats treated on each of these days. This effect shifts from lateral to medial divisions of the entorhinal cortex with later administration of MAM, following a known developmental gradient. Morphological consequences of MAM administration appear to be largely confined to the entorhinal cortex in the groups treated on E9 to E11, although slight reductions of the frontal and occipital neocortex were also observed in these animals. MAM treatment on E12 produces relatively more widespread damage, as reflected among other in a small reduction of brain weight. The described brain abnormalities are not accompanied by obvious phenotypical changes in any, but the E12-treated group. They, moreover, involve cortical thinning, disorganised cortical layering, and abnormal temporal asymmetries. These finding bare some similarity to observations in brains of schizophrenic subjects. The possible relevance of this approach in modeling neurodevelopmental aspects of schizophrenia is discussed.

Rat hippocampal kindling induces changes in the glutamate receptor mRNA expression patterns in dentate granule neurons.

The expression level of the mRNAs encoding the Flip and Flop versions of the AMPA-selective glutamate receptor subunits A, B, C and D was studied using in situ hybridization in the hippocampus of rats kindled by Schaffer collateral/commissural fibre stimulation. The expression levels of the Flip variant of GluR-A, B and C mRNAs were bilaterally enhanced in the dentate granule neurons of fully kindled animals 24 h after the last seizure. These changes were already observed after the sixth kindling stimulation (preconvulsive-stage), but not after a single afterdischarge. Four weeks after the last seizure, when the animals were still hypersensitive to kindling stimulations, only GluR-A Flip expression was enhanced. These results suggest that kindling epileptogenesis is accompanied by an increased number and enhanced sensitivity of the expressed AMPA type glutamate receptors in the fascia dentata, leading to an enhanced excitatory synaptic transmission which may contribute to the process of kindling epileptogenesis.

Immunohistochemical localization of nerve growth factor (NGF) and NGF-receptor in the hypothalamus of adult rats.

In the adult mammalian central nervous system (CNS) the nerve growth factor (NGF) has thus far been associated mainly with the metabolic support and pathophysiology of cholinergic basal forebrain (CBF) neurons. Recently, however, the presence of NGF and NGF mRNA has been demonstrated in the hypothalamus of adult mice. In addition there have been reports on the stimulation of the pituitary-adrenocortical axis by NGF. These and other findings suggest the involvement of NGF in hypothalamic functioning. The aim of the present study was to improve immunohistochemical methodologies for the investigation of NGF and NGF-receptor (NGF-r) in the hypothalamus of adult rats. Our results show NGF and NGF-r expression in various regions of the hypothalamus. Moreover, in some areas, distribution and morphology of immunoreactive neurons suggest neuronal colocalization of the two markers. To study the function of NGF in the hypothalamus, anti-NGF antibody was injected in the area of the paraventricular nucleus. We did not, however, find an effect of treatment on NGF-r immunoreactive neurons in this area.

Effects of time of feeding on recovery of food-entrained rhythms during subsequent fasting in SCN-lesioned rats.

Rats subjected to Eat-Fast (EF) cycles show food-anticipatory rhythms independent from the suprachiasmatic nuclei (SCN). These rhythms do not persist during subsequent ad lib feeding (EE). There are indications for a recovery of rhythmicity during fasting (FF) using a 'memory' paradigm in which FF sessions are alternated with EE. In this study we tested the memory paradigm in SCN-lesioned rats that were fed for 3 hr either during the local day (food access at 14.30 hr) or during the night (food access at 04.30 hr or at 23.00 hr). Food approaches, drinking, wheel-running and body temperature were recorded under constant light. Food-anticipatory rhythms emerged under each EF schedule while the shape of the rhythms differed per schedule. The rhythms disappeared in EE. During subsequent FF the rhythms clearly reappeared in previously day-fed rats, but this was only occasionally observed in previously night-fed rats. Moreover, the phase of the rhythms which did recover in the previously night-fed rats was shifted towards daytime. These data are not fully compatible with the hypothesis of a self-sustained food-entrainable oscillator. It was assumed that hunger-induced responses to environmental daytime stimuli contributed to the overt rhythms.