Microsoft Word - JOHNSTONE_NEUR3X04_2020.docx
The INSTRUCTIONS (Research Proposal)
Please answer the question related to your seminar group.
Your answer must not exceed FOUR A4 pages of text and ONE A4 page of References (any style).
You may use figures and diagrams if they support your response, you may not use previously published figures or images.
Use exactly this formatting for your electronic submission on the CANVAS site
ARIEL font (11 point); BLACK TEXT
PAGE SIZE A4
PAGE MARGINS 2.00cm TOP/ 2.00cm BOTTOM/ 2.00cm LEFT/2.00cm RIGHT
LEFT JUSTIFIED
SINGLE SPACED
_________________________________________________________________________
The QUESTION
This written assessment asks you to write, as though you were a scientist applying for research funding from the Australian Neuroscience Research Council.
Develop a research proposal using experimental animal models that will test the hypothesis that … The stability circuitry, refe
ed to as the “flip-flop circuitry” by Saper et al., is destabilised postpartum.
Your proposed studies should take advantage of modern neuroscience approaches.
Instructions and Directions:
In this assessment you should consider specific aims, significance, innovation and approach.
Remember that your examiners need to be convinced that you have a grasp of the topic and that you can convey your research plan clearly. Even though the research may involve complex relationships you still need to express your ideas as simply as possible.
Your first page should contain the Specific Aims; this will be a description of the background to your studies, an overview of the problem and an overview of your approach, this section is worth 25% of the final marks.
The remainder of your proposal is the Research Strategy, which should contain each of the components listed below, with an emphasis on the approach, significance and innovation in that order of priority. In other words, the examiners are more interested in how you would approach the problem. Avoid lots of “hand-waving” about significance and innovation. Your research strategy is worth 70% of the marks.
Specific Aims (25% of marks)
Describe the background to the problem and study. State concisely the goals of the proposed research and summarize the expected outcome(s), including the impact that the results of the proposed research will have on the research field(s) involved. List succinctly the specific objectives of the research proposed, e.g., to test stated hypotheses, create a novel design, solve a specific problem, challenge an existing paradigm, address a critical ba
ier to progress in the field, or develop new technology.
Research Strategy (75% of marks)
Organize the Research Strategy in the specified order and using the instructions provided below. Start each section with the appropriate section heading—Significance, Innovation, Approach. Cite published experimental details in the Research Strategy section and provide the full references in your References section.
(a) Significance (10%)
· Explain the importance of the problem or critical ba
ier to progress in the field that the proposed project addresses.
· Explain how the proposed project will improve scientific knowledge, technical capability, and/or clinical practice in one or more
oad fields.
· Describe how the concepts, methods, technologies, treatments, or preventative interventions that drive this field will be changed if the proposed aims are achieved.
(b) Innovation (5%)
· Explain how the application challenges and seeks to shift cu
ent research thinking.
· Describe any novel theoretical concepts, approaches or methodologies to be developed or used, and any advantage over existing methodologies, instrumentation.
· Explain any refinements, improvements, or new applications of theoretical concepts, approaches or methodologies, instrumentation or interventions.
(c) Approach (60%)
· Describe the overall strategy, methodology, and analyses to be used to accomplish the specific aims of the project.
· How the data will be collected, analyzed, and interpreted.
· Discuss expected outcomes, potential problems, alternative strategies, and benchmarks for success anticipated to achieve the aims.
References
References to be supplied as a single A4 page, using a consistent in text formatting style.
PII: S XXXXXXXXXX
TRENDS in Neurosciences Vol.24 No.12 December 2001
http:
tins.trends.com XXXXXXXXXX/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S XXXXXXXXXX
726 ReviewReview
Clifford B. Saper*
Thomas C. Chou
Thomas E. Scammell
Dept of Neurology and
Program in Neuroscience,
Harvard Medical School,
Beth Israel Deaconess
Medical Center, Boston,
MA 02215, USA.
*e-mail: csaper@
caregroup.harvard.edu
During World War I, the world was swept by a
pandemic of encephalitis lethargica, a presumed viral
infection of the
ain that caused a profound and
prolonged state of sleepiness in most individuals. The
victims could be awakened
iefly with sufficient
stimulation, but tended to sleep most of the time. A
Viennese neurologist, Baron Constantin von Economo,
eported that this state of prolonged sleepiness was due
to injury to the posterior hypothalamus and rostral
mid
ain1. He also recognized that one group of
individuals infected during the same epidemic instead
had the opposite problem: a prolonged state of insomnia
that occu
ed with lesions of the preoptic area and basal
fore
ain. von Economo further hypothesized that
lesions of the posterior diencephalon could cause the
disease we now call narcolepsy, in which individuals
have a tendency to fall asleep at inappropriate times.
Based on his observations, von Economo predicted that
the region of the hypothalamus near the optic chiasm
contains sleep-promoting neurons, whereas the
posterior hypothalamus contains neurons that promote
wakefulness.
In subsequent years, his observations on the sleep-
producing effects of posterior lateral hypothalamic
injuries were reproduced by lesions in the
ains of
monkeys2, rats3 and cats4; and the insomnia-
producing effects of lateral preoptic–basal fore
ain
injuries were demonstrated in rats3 and cats5.
Injections of the GABA-receptor agonist muscimol into
these areas in cats produced results similar to that of
the lesions, suggesting that wakefulness is promoted
y neurons in the posterior lateral hypothalamus and
sleep by neurons in the preoptic area6. However, the
asic neuronal circuitry that causes wakefulness was
only clearly defined in the 1980s and early 1990s, and
the pathways responsible for the hypothalamic
egulation of sleep began to emerge only in the past
five years. This article focuses on these hypothalamic
switching mechanisms. Other recent publications are
available that discuss the homeostatic and circadian
control of sleep7, the contributions of
ainstem
cholinergic–monoaminergic interactions to rapid eye
movement (REM)–non-REM (NREM) sleep
oscillations8–10, and the role of the dopaminergic
system in sleep regulation11. Our model of the
hypothalamic switching circuitry provides an effecto
mechanism by which many of these other systems
produce or prevent sleep.
The cholinergic and monoaminergic substrates
of arousal
In the years after World War II, Moruzzi, Magoun and
many others contributed to identifying an ascending
pathway that regulates the level of fore
ain
wakefulness12. Transection of the
ainstem at the
midpons or below did not reduce arousal, whereas
slightly more rostral transections at a midcollicula
level caused an acute loss of wakefulness. The wake-
promoting outflow from this crucial slab of tissue at
the rostral pontine–caudal mid
ain interface was
traced by anatomical and physiological techniques
through the paramedian mid
ain reticular formation
to the diencephalon, where it divided into two
anches. One pathway innervated the thalamus, and
the second extended into the hypothalamus. Although
this arousal system was termed the ascending
eticular activating system, in fact its origins were
identified only recently by the availability of modern
neuroanatomical tracer methods combined with
immunohistochemistry (Fig. 1).
The main origin of the thalamic projection from the
caudal mid
ain and rostral pons was identified as the
cholinergic pedunculopontine and laterodorsal
tegmental nuclei (PPT–LDT)13–15. This population of
cholinergic neurons projects in a topographic fashion to
the thalamus, including the intralaminar nuclei16–18,
ut also to the thalamic relay nuclei and the reticula
nucleus of the thalamus. The reticular nucleus is
thought to play a key role in regulating thalamic
activity, and the cholinergic influence is thought to be
crucial in activating thalamocortical transmission19.
The activity of the PPT–LDT neurons varies with
different behavioral states. During wakefulness,
when the cortical electroencephalogram (EEG) shows
low-voltage fast activity, many PPT–LDT neurons fire
apidly (Table 1). As the individual goes to sleep, the
EEG waves become slower and larger; during this
period, few PPT–LDT neurons are active. Periodically
during the night, the individual enters a very
The sleep switch: hypothalamic
control of sleep and wakefulness
Clifford B. Saper, Thomas C. Chou and Thomas E. Scammell
More than 70 years ago, von Economo predicted a wake-promoting area in the
posterior hypothalamus and a sleep-promoting region in the preoptic area.
Recent studies have dramatically confirmed these predictions. The
ventrolateral preoptic nucleus contains GABAergic and galaninergic neurons
that are active during sleep and are necessary for normal sleep. The posterio
lateral hypothalamus contains orexin/hypocretin neurons that are crucial fo
maintaining normal wakefulness. A model is proposed in which wake- and
sleep-promoting neurons inhibit each other, which results in stable
wakefulness and sleep. Disruption of wake- or sleep-promoting pathways
esults in behavioral state instability.
TRENDS in Neurosciences Vol.24 No.12 December 2001
http:
tins.trends.com
727Review
different state of active sleep, in which there are rapid
eye movements (REM sleep), a loss of muscle tone,
except for the muscles involved in respiration, and a
low-voltage fast EEG, which resembles a waking
state. The PPT–LDT are released from tonic
monoamine-mediated inhibition and hence fire
apidly during REM sleep8–10,20.
If the thalamocortical system is activated in both
wakefulness and REM sleep, what is the difference
etween these two states? One key distinction is the
activity in the hypothalamic
anch of the ascending
arousal system (Fig. 1). Cell groups in the caudal
mid
ain and rostral pons that contribute to this
projection include the noradrenergic locus coeruleus
and the serotoninergic dorsal and median raphé
nuclei, as well as the para
achial nucleus21. Thei
axons run through the lateral hypothalamus, where
they are joined by histaminergic projections from the
tuberomammillary nucleus (TMN). Other neurons in
the lateral hypothalamic area, some of which contain
the peptide neurotransmitters orexin (also known as
hypocretin)22 or melanin-concentrating hormone23,
join this projection, as do axons from the basal
fore
ain cholinergic nuclei (Fig. 1). Each of these
pathways projects diffusely to the cortex of the entire
cere
al hemisphere.
The neurons in the monoaminergic cell groups
have been closely studied for their relationship to
ehavioral state. Neurons in the locus coeruleus, the
dorsal raphé nucleus and the TMN all fire at
elatively characteristic rates, which are state
dependent24–27. All three groups fire fastest during
wakefulness, slow down with the EEG during