Breaking News
December 12, 2018 - 10 Facts on Patient Safety
December 12, 2018 - Poorest dying nearly 10 years younger than the rich in ‘deeply worrying’ trend for UK
December 12, 2018 - Innovative care model for children with ASD reduces use of behavioral drugs in ED
December 12, 2018 - Simple measures to prevent weight gain over Christmas
December 12, 2018 - Research advances offer hope for patient-tailored AML treatment
December 12, 2018 - Researchers discover a ‘blind spot’ in atomic force microscopy
December 12, 2018 - Sprayable gel could help prevent recurrences of cancer after surgery
December 12, 2018 - SLU researchers explore how fetal exposure to inflammation can alter immunity in newborns
December 12, 2018 - How do patients want to discuss symptoms with clinicians?
December 12, 2018 - Zinc chelation may be able to deliver drug to insulin-producing cells
December 12, 2018 - Brigham researchers develop automated, low-cost tool to predict a woman’s ovulation
December 12, 2018 - Some people with Type 2 diabetes may be testing their blood sugar more often than needed
December 12, 2018 - Slow-growing type of glioma may be vulnerable to immunotherapy, suggests study
December 12, 2018 - Study provides new information regarding microRNA function in cellular homeostasis of zebrafish
December 12, 2018 - Study provides new understanding of mysterious ‘hereditary swelling’
December 12, 2018 - Researchers shed new light on how to combat Shiga and ricin toxins
December 12, 2018 - Pregnant Women Commonly Refuse Vaccines
December 12, 2018 - Drug treatment could offer new hope for some patients with brain bleeding
December 12, 2018 - Health care financial burden of animal-related injuries is growing, study says
December 12, 2018 - Macrophage cells could help repair the heart following a heart attack, study finds
December 12, 2018 - Researchers develop new system for efficiently producing human norovirus
December 12, 2018 - New artificial intelligence-based system to differentiate between different types of cancer cells
December 11, 2018 - Brazilian professors propose guidelines for therapeutic use of melatonin
December 11, 2018 - Healthy Lifestyle Lowers Odds of Breast Cancer’s Return
December 11, 2018 - New research identifies two genes linked to serious congenital heart condition
December 11, 2018 - NIH Director talks science, STEM careers with preteens
December 11, 2018 - Disabling a Cellular Antivirus System Could Improve Gene Therapy
December 11, 2018 - New tool swiftly provides accurate measure of patients’ cognitive difficulties
December 11, 2018 - NICE releases new guidelines for diagnosis and management of COPD
December 11, 2018 - Without Obamacare penalty, think it’ll be nice to drop your plan? Better think twice
December 11, 2018 - Researchers capture high-resolution X-ray and NMR image of key immune regulator
December 11, 2018 - Natural flavonoid is effective at treating leishmanisis infections, study shows
December 11, 2018 - Avoidant grievers unconsciously monitor and block mind-wandering contents, study shows
December 11, 2018 - Study identifies how hantaviruses infect lung cells
December 11, 2018 - Improving PTSD care through genetics
December 11, 2018 - Dermatology providers show interest in recommending cannabinoids to patients
December 11, 2018 - Researchers to study effects of electroconvulsive therapy on Alzheimer’s patients with aggression
December 11, 2018 - Four dried fruits have lower glycemic index than starchy foods, study finds
December 11, 2018 - Optimization of drug dose sizes can reduce pharmaceutical wastage
December 11, 2018 - Ultrarestrictive opioid prescribing strategy linked with reduction in number of pills dispensed
December 11, 2018 - PET scans to optimize tuberculosis meningitis treatments and personalize care, study finds
December 11, 2018 - Researchers aim to identify and target high blood pressure indicators
December 11, 2018 - Researchers identify immune cell subset that may drive chronic inflammation
December 11, 2018 - Ezogabine treatment reduces motor neuron excitability in ALS patients, study shows
December 11, 2018 - One implant, two prices. It depends on who’s paying.
December 11, 2018 - Standardizing feeding practices improves growth trends for micro-preemies
December 11, 2018 - COPD Tied to Obesity in Male, Female Never-Smokers
December 11, 2018 - Flossing: Information for Caregivers
December 11, 2018 - Does breastfeeding hormone protect against type 2 diabetes?
December 11, 2018 - Educating future doctors to prescribe physical activity for their patients
December 11, 2018 - Krystal 2000 microplate design improves fluorescence and luminescence measurement
December 11, 2018 - FDA clears mobile medical app to help increase retention in recovery program for opioid use disorder
December 11, 2018 - Overcoming Challenges in High-Speed Centrifugation Experiments
December 11, 2018 - Study shows link between neighborhoods’ socioeconomic status and dietary choices
December 11, 2018 - Lower BMI before obesity surgery predicts greater post-operative weight loss, study finds
December 11, 2018 - Obesity May Be Driving Rise in Uterine Cancers
December 11, 2018 - Antioxidants may prevent cognitive impairment in diabetes
December 11, 2018 - Study discovers link between meditation and how individuals respond to feedback
December 11, 2018 - Researchers identify potential diagnostic tool for Alzheimer’s disease
December 11, 2018 - Oral cancer prognostic signature identified
December 11, 2018 - How Can I Find Out What Caused My Miscarriage?
December 11, 2018 - Novel personalized medicine tool for assessing inherited colorectal cancer syndrome risk developed
December 11, 2018 - Study uncovers 11 new genes associated with epilepsy
December 11, 2018 - Filling research gaps could help develop more disability-inclusive workplaces
December 11, 2018 - Cartilage tissue engineering brings good news for patients with cartilage defects
December 11, 2018 - Novel 3D printing workflow helps predict leaky heart valves
December 11, 2018 - Imagination can help overcome fear and anxiety-related disorders, shows study
December 11, 2018 - Are caries linked to political regime?
December 11, 2018 - Leader in Diabetes Clinical Trials Wins Naomi Berrie Award
December 11, 2018 - Scientists discover cellular mechanism that triggers pneumonia in humans
December 11, 2018 - Increasing mental health problems related to drug use in over 55’s
December 11, 2018 - High-intensity interval exercise could help combat cognitive dysfunction in obese people
December 11, 2018 - Annual flu shot can save lives of heart failure patients
December 11, 2018 - Researchers compare health outcomes for VA and non-VA hospitals
December 11, 2018 - Recommendations Developed for Psoriatic Arthritis Treatment
December 11, 2018 - Genetic analysis links obesity with diabetes, coronary artery disease
December 11, 2018 - Study shows that having genetic information can affect how the body responds
December 11, 2018 - UNAIDS Report: 9 Million Are Likely HIV Positive And Don't Know It
December 11, 2018 - Lund University researchers succeed in obtaining dendritic cells by direct reprogramming
December 11, 2018 - Breast tumors recruit bone marrow cells to boost their growth, study reveals
The hippocampus is crucial for forming non-hippocampal long-term memory during sleep

The hippocampus is crucial for forming non-hippocampal long-term memory during sleep

image_pdfDownload PDFimage_print
Effects of post-encoding sleep vs. wakefulness on memory in the NOR and OPR tasks. a) During the encoding phase of the two tasks rats explored two identical objects in the arena for 10 minutes. Encoding was followed by a two-hour interval in which the rat either slept or remained awake. Retrieval was tested immediately after the 2-hour post-encoding interval (recent memory), 1 week (NOR only) and 3 weeks later (remote memory). During retrieval, the rat explored the arena for 5 minutes. To test NOR retrieval one of the two objects (from the encoding phase) was replaced by a novel object (arrow). Recognition memory was indicated when the rat spent more time exploring the novel object than the familiar object – where exploration during the first minute was most sensitive for novelty exploration. To test OPR retrieval, one of the objects was displaced (relative to its location at encoding, arrow) and memory for the place was indicated when the rat spent more time exploring the displaced object than the stationary object. b) Mean + s.e.m. discrimination ratios during the first minute of exploration for NOR and OPR at the recent (2 hour) and remote (1 or 3 weeks after) retrieval tests. NOR memory benefited from post-encoding sleep (red bars: compared with wake – grey) only at the 3 weeks retrieval test, when NOR memory had decayed in the wake conditions. By contrast, OPR memory benefited from sleep at both recent and remote testing. Credit: Nature. doi:10.1038/s41586-018-0716-8

A longstanding division exists between hippocampus-dependent and non-hippocampus dependent memory since only the latter can be acquired and retrieved in the absence of normal hippocampal functions. In agreement with the familiar concept of “sleeping on a problem,” hippocampal-dependent memory consolidation is strongly supported by sleep. In a new study conducted by Anuck Sawangjit and colleagues, formation of long-term representation in a rat model of non-hippocampal memory was shown to depend on sleep and on the activation of hippocampus-dependent mechanisms during sleep.

The researchers used rats encoded with non-hippocampus-dependent (novel-object recognition, NOR) and hippocampus-dependent (object-place recognition, OPR) memories prior to a two-hour period of sleep and wakefulness. Memory was either tested immediately or remotely after one or three weeks. While object-place recognition memory was stronger for rats that had slept after encoding at both timepoints of testing, novel object-recognition memory only profited from sleep three weeks after encoding. At this timepoint (3 weeks), object-recognition memory was preserved in rats that slept after encoding and not in those that had been awake. Of note, intrahippocampal injection of muscimol (a psychoactive constituent) inactivated the hippocampus during post-encoding sleep, and abolished sleep-induced enhancement of remote novel-object recognition memory. In contrast, injection of muscimol before remote retrieval or memory encoding did not affect test performance, indicating that encoding and retrieval of novel-object recognition memory were hippocampus-independent. Consistent with the view that neuronal memory replay during slow-wave sleep contributed to long-term memory formation, remote novel-object memory recognition was associated with spindle activity during post-encoding slow-wave sleep in the study.

The distinction between hippocampus-dependent and non-hippocampus dependent forms of memory was highlighted in medical research when a patient underwent bilateral removal of large portions of the hippocampus and suffered severe anterograde amnesia. While encoding and retrieval of hippocampus-dependent memories required the hippocampus, this was not always the case for non-hippocampus dependent memory. Non-hippocampus dependent memory consisted of heterogenous memories, including motor skills and fear conditioning. Recent advances in memory research alongside the standard consolidation theory assume that episodes of memory were initially encoded into the hippocampal networks but redistributed across days, weeks and months to the neocortex for long-term storage during consolidated representation to thereby become independent of the hippocampus.

For hippocampus-dependent memory, an active systems consolidation process was proposed based on the findings that neural representation of freshly encoded memories replayed during subsequent slow-wave sleep (SWS). By mechanism, neural replay originating from hippocampus networks together with sharp-wave ripples and thalamic spindles promoted the transmission of memory information. Repetitive occurrence enabled their gradual redistribution in extrahippocampal networks. The role of sleep during non-hippocampus-dependent memory is less well understood.

**The hippocampus is crucial for forming non-hippocampal long-term memory during sleep
Verifying cannula location and muscimol spreading. a) Coronal brain section showing the location of cannula in the dorsal hippocampus (black arrow) with the position of guide cannula in the overlying cortex. b) Coronal brain section showing the spread of muscimol (red) after infusion into the hippocampus. The infusion protocol was similar in the behavioral experiments. After implantation of the guide cannula into the dorsal hippocampus, animals were infused with fluorophore conjugated muscimol. Animals were intracardially perfused after infusion and brains post-fixed in paraformaldehyde (4%) for 24 hours. Brains were sliced with a vibratome to obtain sections for histopathology and fluorescent-microscopy imaging. Credit: Nature, doi:10.1038/s41586-018-0716-8

In the study, Sawangjit et al, compared the effects of post-encoding wakefulness on consolidation of non-hippocampus-dependent and hippocampus-dependent forms of memory in rats to understand the evolution of consolidation effects with time. To accomplish this, the researchers used the novel-object recognition (NOR) task and object-place recognition (OPR) task as tests to determine non-hippocampus-dependent and hippocampus-dependent-memory. Performance on the NOR task typically relied on the perirhinal cortex, normal hippocampal functions were not necessary to encode or retrieve NOR memory in rats according to preceding studies. During a two-hour interval, the rats either slept or remained awake after task encoding. Retrieval was tested immediately after the two-hour interval or conducted after one week (NOR only), or three weeks later (remote tests) to test long-term memory. The NOR memory did not differ between sleep and awake states, but in contrast OPR memory significantly enhanced after sleep only and not while awake. Repeated reactivation of newly encoded hippocampal representation during subsequent slow-wave-sleep (SWV) had an impact on the consolidating effect of sleep on hippocampus-dependent spatial memory.

Previous evidence also suggested that hippocampus-dependent and non-hippocampus-dependent memory systems interacted during consolidation. The researchers therefore investigated if hippocampal activity critically contributed to the integration of non-hippocampus-dependent memory by reversibly inactivating the function of the hippocampus. For this, the rats were infused with muscimol (a psychoactive constituent) into the dorsal hippocampus during sleep after encoding the NOR task.

The effects of reversibly inactivating the hippocampus on NOR memory. Left, procedures; right, mean + s.e.m. discrimination ratios, with overlaid dot plots. a) To suppress hippocampal activity, muscimol was bilaterally infused (for 2 min) into the dorsal hippocampus, either during the post-encoding interval upon the first occurrence of continuous SWS (top), or 15 min before remote retrieval testing 3 weeks after encoding (bottom). Hippocampal inactivation during post-encoding sleep (red bar) abolished remote NOR memory whereas inactivation before retrieval testing (blue bar) was ineffective. Grey bar, vehicle injection. b) Muscimol (purple bar) was infused shortly after encoding while the rats remained awake during the 2-h post-encoding interval. Retrieval was tested 1 week later. Compared with untreated wake control rats (empty bar), which had intact hippocampal function and stayed awake during the post-encoding interval, hippocampal inactivation did not disturb but enhanced NOR performance. Timing (with reference to encoding), dosage and procedures of muscimol infusion were the same as in (a). c) Muscimol (or vehicle) was infused 15 min before retrieval testing of recent NOR memory (top) or 15 min before the encoding phase (bottom). Retrieval was tested 30 min after encoding (rats stayed awake during this interval). Hippocampal inactivation does not affect retrieval of recent NOR memory either during retrieval or during encoding. Credit: Nature, doi:10.1038/s41586-018-0716-8.

Three weeks after, during remote retrieval testing, rats who had received muscimol injection into the hippocampus during sleep after learning did not show significant NOR memory. Comparatively, remote NOR memory was preserved in animals injected with the vehicle at the same timepoint. The result demonstrated that the hippocampus was crucial to form persistent NOR memory during sleep. Previous discrepancies of the hypothesis were thus resolved by the new results observed in the study, to show that the formation of long-term NOR memory relied on a hippocampal mechanism that was specifically active during sleep. Combined results confirmed that persistent long-term NOR memory formation relied on a hippocampal mechanism that was specifically active during sleep.

In the architecture of post-encoding sleep, results were comparable to previous studies, and analyses revealed that remote NOR memory retrieval strongly correlated with measures of spindle activity during slow-wave-sleep (SWS). The combined results agreed with the idea that muscimol prevented long-term memory formation by suppressing hippocampal ripples as well as its associated reactivation during SWS. The findings by Sawangjit et al. did not completely rule out contributions of REM-sleep-related mechanisms, although the concept was not addressed in the present study.

Contribution of post-encoding slow wave sleep to remote NOR memory. Contribution of post-encoding slow wave sleep to remote NOR memory. a) NOR performance (discrimination ratio) at the 3-week retrieval test correlated with the number of sleep spindles during SWS (top) and spindle mean duration during the 2-h post-encoding interval (middle), as well as with spindle mean duration during the first 30 min of post-encoding sleep (bottom). b) Intrahippocampal local field potentials (LFPs) were recorded in additional rats to examine the effects of bilateral intrahippocampal infusion of muscimol (Mus) (versus vehicle, Veh) on (from left to right) ripples, spindles, and slow oscillations (SO) in hippocampal networks during SWS. Muscimol decreased the total number and density of ripples, as well as spindle power and slow oscillation amplitude. Credit: Nature, doi:10.1038/s41586-018-0716-8.

While ample evidence already exists to indicate involvement of the hippocampus during memory consolidation for their retention and retrieval with normal hippocampal function. New results in the study indicated necessity of the normal hippocampus to form persistent long-term representations on a task that is classified non-hippocampus-dependent. To understand how the hippocampus contributed to long-term NOR memory formation, the researchers proposed that during sleep the hippocampus likely boosted object representation by activating context-related representations instead of direct perirhinal object memory enhancement. This proposal was supported by the observed correlation of long-term NOR performance with post-encoding sleep spindle activity.

Comprehensive findings of the study suggested a common hippocampal mechanism that boosted consolidation in both hippocampus-dependent and non-hippocampus-dependent memory systems by reactivating contextual features. Since non-hippocampal-dependent memory is heterogenous (motor skills, fear conditioning etc.), other memories of the nature require investigations so as to support the proposed general hippocampal mechanism of long-term memory formation.


Explore further:
Nested sequences: An indispensable mechanism for forming memories

More information:
Anuck Sawangjit et al. The hippocampus is crucial for forming non-hippocampal long-term memory during sleep, Nature (2018). DOI: 10.1038/s41586-018-0716-8

Robert Stickgold. Sleep-dependent memory consolidation, Nature (2005). DOI: 10.1038/nature04286

Giulio Tononi et al. Sleep and the Price of Plasticity: From Synaptic and Cellular Homeostasis to Memory Consolidation and Integration, Neuron (2014). DOI: 10.1016/j.neuron.2013.12.025

Journal reference:
Nature

Neuron

Tagged with:

About author

Related Articles