Imaging synaptic memory formation using a novel drug-controlled reporter

 Rat hippocampal neuron with Endogenous Arc by confocal microscop

 

Introduction

The immense capacity and specificity of memory storage in the mammalian brain is thought to depend on the plasticity of synaptic connections. Dysfunction of synaptic plasticity is implicated in a range of disorders from Alzheimer’s disease to mental retardation and development of chronic pain states.  Understanding how neural activity patterns are translated into lasting changes in synaptic connectivity is therefore one of the most important challenges in basic and clinical neuroscience.

Long-term memory relies on lasting changes in synaptic connectivity, and these synaptic modifications depend on new gene expression and protein synthesis. Arc (activity-regulated cytoskeleton-associated protein), is an immediate-early gene that is rapidly induced upon neuronal activity. Arc transcription, translation, and protein function provides a finely-tuned system for converting neuronal activity patterns into protein synthesis-dependent synaptic plasticity and memory storage. By a biological logic that is not yet understood, Arc synthesis controls both long-term potentiation (LTP) and long-term depression (LTD) of synaptic connections.

Aims

A novel, drug-controllable tool for visualizing new protein synthesis, called TimeSTAMP, is used to visualize and monitor local synthesis and trafficking of Arc in hippocampal neuronal cells undergoing functional changes such as LTP and LTD in the brain of rats. This approach will give us fundamental new insights into how memory operates at the synaptic level.

In the TimeSTAMP reporter, the cassette encoding the protein of interest, e.g. Arc, is followed by a sequence-specific protease, an epitope tag and a fluorescent protein called Venus. The protease in this cassette can be specifically inhibited by the cell permeant drugs. Upon translation of Arc, protease activity cleaves the epitope tag and a part of the Venus fluorescent protein effectively disallowing detection of signal. In the presence of inhibitor the entire fluorescent protein is preserved, so that it can mature and emit fluorescent light upon excitation, thus allowing selective detection of newly synthesized proteins both by fluorescence and epitope tagging.

Methods

TimeSTAMP allows live time-lapse imaging of new protein synthesis using the fluorescent protein signal in addition to detection of the epitope tagged protein in fixed samples. In this study, in vitro hippocampal neurons dissected out from rat embryos are transfected with this drug-controllable reporter, followed by chemical LTP stimulation and imaging of the temporal and spatial characteristics of Arc by confocal microscopy.

Adrian Szum

Supervisor: Prof. Clive Bramham, Neuroscience

Symptomer på ADHD er vanlig hos deprimerte ungdommer

Young people
Young people

Ungdomsalder er en periode i livet der de fleste opplever utfordringer knyttet til regulering av følelser og atferd. I denne aldersgruppen er det derfor ofte spesielt vanskelig å skille mellom normale reaksjoner og reaksjoner som gir grunn til bekymring og innsats fra hjelpeapparatet. Også når ungdommer forteller om alvorlige problem kan det være vanskelig å definere disse innenfor en gitt diagnostisk kategori.

Overlapp og kjønnsforskjeller i ungdoms rapportering av emosjonelle og atferdsmessige problem ble nylig undersøkt i en studie av deltakere i ung@hordaland studien (n = 9614). Her svarte mer enn ni tusen ungdommer på alle spørsmål som inngår i et spørreskjema som kartlegger depressive plager (kortformen av Mood and Feelings Questionnaire – sMFQ) og symptomer på ADHD (Adult ADHD Self-Report Scale – ASRS). Alvorlighetsgrad av depresjon ble målt ved en totalskåre på sMFQ, og denne ble klart påvirket av hvert ekstra ADHD symptom som ungdommen rapporterte. Høy  sMFQ skåre (≤ 90%) ble brukt som tegn på depresjon. Blant disse rapporterte ~ 20% et såpass høyt antall ADHD symptom at det var grunn til å tro at de også tilfredstilte denne diagnosen. Selv om jentene rapporterte høyere skårer enn guttene på begge spørreskjemaene, viste guttene like omfattende ADHD relaterte problem som jentene hvis de samtidig viste tegn på depresjon.

Studien gir sterke argumenter for et bredt perspektiv på mental helse ved kartlegging av emosjonelle og atferdsmessige problemer hos ungdommer. Videre understreker omfanget av de problemer som rapporteres betydningen av forebyggende arbeid, både for å minske det stigma som fremdeles er forbundet med psykiske plager, og for å tidlig oppdage og behandle de som trenger det. Mange tidligere studier har vist oss at tidlig innsats er avgjørende for å hindre mer omfattende problemer i voksen alder.

Lundervold, AJ, Hinshaw, SP, Sørensen, L, Posserud, M. (2016). Co-occurring symptoms of attention deficit hyperactivity disorder (ADHD) in a population-based sample of adolescents screened for depression. BMC Psychiatry, 2016 Feb 25;16(1):46. doi: 10.1186/s12888-016-0739-3.

Astri Lundervold, professor og spesialist i klinisk nevropsykologi.

Book recommendation – The Reason I Jump

Naoki Higashida is diagnosed with autism. He is unable to speak, however at the age of 13 he wrote “The Reason I Jump” by the use of a Japanese character grid. While answering questions often addressed to persons with autism spectrum disorders, Higashida challenges common preconceptions and offers the reader reflection on the topic.

The book was translated to English in 2013, when it became a New York Times bestseller and received international attention. In the following book review, the journalist describes how “The Reason I Jump” provided a new view of the behavior of her own sister, who is diagnosed with an autism spectrum disorder: Review: The Reason I Jump

The “Reason I Jump” is easy-read, and is recommended to anyone interested in getting a clinical perspective on autism spectrum disorders.

Book_TheReasonIJumped

 

 

 

 

 

 

 

Elisabeth Kvadsheim

Schizofrenia risk from C4 genes

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“A new study, published in Nature this January, Schizophrenia risk from complex variation of complement component 4links , complement component 4 (C4) genes to schizophrenia. C4 genes are important in the major histocompatibility complex (MHC). C4 was found to mediate synapse elimination (called pruning) in development after birth, in mice. These findings might therefore help to explain the reduced number of synapses in brains of humans with schizophrenia.

(Sekar et al., 2016)

Lynn Marquardt

Science 2.0: The case against science in biomedicine

As the editor of one of the most prestigious peer-reviewed medical journals in the world (The Lancet) said, “the case against science is straightforward: much of the scientific literature, perhaps half, may simply be untrue.” 1 This is Science 2.0.

Science 2.0 does not bother with the old phenomena of sane hypotheses, experiments, interpretation of results or reasonable conclusions. Those are the limitations of Science 1.0, which prompted the development of the newer version of Science. Science 2.0 is easy to implement as it has the “advantages” of not being based on facts, the experiments being manipulated to support the conclusions and the time-consuming peer-reviews being omitted. In addition, Science 2.0 is also accepting “statistical fairy-tales” about significance1 and it does not care about negative findings (no matter how informative they may be).Negativedata

Since 2015, we are even able to study human health in space as NASA has selected 10 scientists from 12 Universities to examine how zero-gravity may affect the human body (https://www.nasa.gov/twins-study/about;http://time.com/3843801/space-twins-science-kelly/). The concept of this study is very interesting, but it is based on 1 (one!) twin pair. So, there are 10 scientists and 2 participants. This may be the coolest twin study ever, but, most probably, the least statistically powered one in human history.

Science 2.0 is quite alarming: all of its studies are used to develop drugs/vaccines to supposedly help people, train medical staff, educate students and much more. “It is simply no longer possible to believe much of the clinical research that is published, or to rely on the judgment of trusted physicians or authoritative medical guidelines.”2

“In august 2015, the publisher Springer retracted 64 articles from 10 different subscription journals“3, after editorial checks uncovered peer-review fraud. Since 2012, “more than 250 articles have been retracted because of fake reviews — about 15% of the total number of retractions.”3 And there are also cases of data fabrication (http://retractionwatch.com/2015/06/17/columbia-biologists-deeply-regret-nature-retraction-after-postdoc-faked-74-panels-in-3-papers/).

Peter Higgs, who won the Nobel prize for physics in 2013, has famously said: “I wouldn’t be productive enough for today’s academic system.”4 “He would almost certainly have been sacked had he not been nominated for the Nobel in 1980”4 as the British physicist published less than 10 papers between 1964 and 2013.4 Despite such publication record, the University’s authorities decided to keep employing Peter Higgs, because he “might get a Nobel prize – and if he doesn’t” they “can always get rid of him.”4

So, why is it that “individual scientists, including their most senior leaders, do little to alter a research culture that occasionally veers close to misconduct”?1 “Can bad scientific practices be fixed?”1 “One of the most convincing proposals came from outside the biomedical community. Tony Weidberg is a Professor of Particle Physics at Oxford. Following several high-profile errors, the particle physics community now invests great effort into intensive checking and rechecking of data prior to publication. By filtering results through independent working groups, physicists are encouraged to criticise. Good criticism is rewarded.”1 Could good criticism save the science? Let us know your thoughts in the comments below!

1http://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736%2815%2960696-1.pdf

2http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2964337/pdf/pmed.1000355.pdf

3http://www.nejm.org/doi/pdf/10.1056/NEJMp1512330

4http://www.theguardian.com/science/2013/dec/06/peter-higgs-boson-academic-system

 

Tetyana Zayats

 

Alternative pharmacological strategies for adult ADHD treatment: a systematic review.

COLOURBOX2839548ADHD is a common (~3.5% in adulthood and ~5% in childhood) childhood onset neuropsychiatric condition, leading to high disability because of the frequent psychiatric co-morbidities such as substance abuse, major depression and learning disabilities. Thus, the treatment of ADHD is of high relevance to our society, especially as untreated ADHD has been linked to unemployment, criminality and suicidal attempts. To date, the most effective pharmacological therapy includes methylphenidate and atomoxetine, chemical compounds that affect dopaminergic and noradrenergic neurotransmission. But it is important to consider and study the alternative drugs as they may provide help in dealing with resistant ADHD symptoms and/or co-morbid conditions. The following article provides comprehensive overview of such alternatives: Alternative pharmacological strategies for adult ADHD treatment: a systematic review. In short, amphetamines, antidepressants and metadoxine may be considered suitable pharmacological treatments for symptoms of ADHD and its co-morbid conditions.

Tetyana Zayats

Rapport fra konferanse om nanomedisin

Foto: Claude Mansiot
Foto: Claude Mansiot

Ved foten av Alpene i den franske byen Grenoble, ble «European Nanomedicine Meeting» arrangert. Konferansen samlet forskere innen medisin, nanoteknologi, farmasi og biokjemi. De fleste kom fra Europa, men noen var også invitert fra USA. Mange interessante foredrag ble holdt, og temaene spredte seg fra utviklingen av nanomaterialer til kliniske studier av nanoprodukter. Arwyn Jones fortalte om hvordan cellene i kroppen tar opp nanopartikler og hvordan celle-penetrerende peptider (CPP) kan forbedre opptaket slik at legemiddelet, som nanopartiklene bærer på, kan leveres til riktig sted inni cellene.

Foto: Lars Herfindal
Foto: Lars Herfindal

Vi var en gjeng på fire som reiste fra Bergen, Maite Bezem og Fredrik G. Johannessen fra Biogjenkjenning, og presenterte våre prosjekter på poster. Våre postere handlet om biologisk nedbrytbare nanopartikler som brukes til å pakke inn tyrosin hydroksylase, også kalt TH. TH er et enzym og kan beskrives som en molekylær maskin. Kroppen trenger det til å produsere lykkemolekylet dopamin. Dopamin er også et signalstoff som hjernen trenger for å kunne styre kroppens bevegelser. Dopaminnivået kan være påvirket i noen sykdommer, blant annet Parkinsons sykdom og ADHD.

Tekst: Maite (Maria Teresa) Bezem (stipendiat, Biogjenkjenning)

KGJN til stede på medisinstudentenes forskningskonferanse, Frampeik

Kvadsheim holdt en presentasjon om hjerteratevariabilitet hos barn med ADHD og angst
Kvadsheim holdt en presentasjon om hjerteratevariabilitet hos barn med ADHD og angst

30. oktober til 1. november ble medisinstudentenes årlige forskningskonferanse, Frampeik, avholdt. De fire byene Oslo, Bergen, Trondheim og Tromsø veksler på å avholde arrangementet, og i år var det idylliske Tromsø sin tur.

Elisabet Kvadsheim, forskerlinjestudent ved UiB og medlem av KGJN, deltok på konferansen. Forskerlinjen gir medisinstudenter mulighet til å arbeide i en forskningsgruppe parallelt med studiene, og i år har Kvadsheim fulltidspermisjon for å fokusere på forskningen. Hun undersøker hvordan det autonome (ikke-viljestyrte) nervesystemet fungerer hos barn og ungdom med ADHD og angst, ved bruk av et mål kalt hjerteratevariabilitet.

Frampeik gir medisinstudenter som forsker muligheten til å presentere sine prosjekter. Det var et stort spenn i tematikken – alt fra biomarkører og medikamentutprøving til Kvadsheims forskning på ADHD. Kvadsheim fikk flere spørsmål fra salen etter presentasjonen, som kan tyde på at deltakerne syntes dette er et viktig og interessant forskningsområde.

Daniel Jensen