Posts Tagged ‘mouse’

Neuroscientists at Indiana University have reported the first evidence that non-human animals can mentally replay past events from memory. The discovery could help advance the development of new drugs to treat Alzheimer’s disease.

The study, led by IU professor Jonathon Crystal, appears today in the journal Current Biology.

“The reason we’re interested in animal memory isn’t only to understand animals, but rather to develop new models of memory that match up with the types of memory impaired in human diseases such as Alzheimer’s disease,” said Crystal, a professor in the IU Bloomington College of Arts and Sciences’ Department of Psychological and Brain Sciences and director of the IU Bloomington Program in Neuroscience.

Under the current paradigm, Crystal said most preclinical studies on potential new Alzheimer’s drugs examine how these compounds affect spatial memory, one of the easiest types of memory to assess in animals. But spatial memory is not the type of memory whose loss causes the most debilitating effects of Alzheimer’s disease.

“If your grandmother is suffering from Alzheimer’s, one of the most heartbreaking aspects of the disease is that she can’t remember what you told her about what’s happening in your life the last time you saw her,” said Danielle Panoz-Brown, an IU Ph.D. student who is the first author on the study. “We’re interested in episodic memory — and episodic memory replay — because it declines in Alzheimer’s disease, and in aging in general.”

Episodic memory is the ability to remember specific events. For example, if a person loses their car keys, they might try to recall every single step — or “episode” — in their trip from the car to their current location. The ability to replay these events in order is known as “episodic memory replay.” People wouldn’t be able to make sense of most scenarios if they couldn’t remember the order in which they occurred, Crystal said.

To assess animals’ ability to replay past events from memory, Crystal’s lab spent nearly a year working with 13 rats, which they trained to memorize a list of up to 12 different odors. The rats were placed inside an “arena” with different odors and rewarded when they identified the second-to-last odor or fourth-to-last odor in the list.

The team changed the number of odors in the list before each test to confirm the odors were identified based upon their position in the list, not by scent alone, proving the animals were relying on their ability to recall the whole list in order. Arenas with different patterns were used to communicate to the rats which of the two options was sought.

After their training, Crystal said, the animals successfully completed their task about 87 percent of the time across all trials. The results are strong evidence the animals were employing episodic memory replay.

Additional experiments confirmed the rats’ memories were long-lasting and resistant to “interference” from other memories, both hallmarks of episodic memory. They also ran tests that temporarily suppressed activity in the hippocampus — the site of episodic memory — to confirm the rats were using this part of their brain to perform their tasks.

Crystal said the need to find reliable ways to test episodic memory replay in rats is urgent since new genetic tools are enabling scientists to create rats with neurological conditions similar to Alzheimer’s disease. Until recently, only mice were available with the genetic modifications needed to study the effect of new drugs on these symptoms.

“We’re really trying push the boundaries of animal models of memory to something that’s increasingly similar to how these memories work in people,” he said. “If we want to eliminate Alzheimer’s disease, we really need to make sure we’re trying to protect the right type of memory.”

https://news.iu.edu/stories/2018/05/iub/releases/10-scientists-find-first-evidence-animals-can-mentally-replay-past-events.html

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Pinpoint stimulation of a cluster of nerve cells in the brains of mice encouraged timid responses to a perceived threat, whereas stimulation of an adjacent cluster induced boldness and courage.

Researchers at the Stanford University School of Medicine have identified two adjacent clusters of nerve cells in the brains of mice whose activity level upon sighting a visual threat spells the difference between a timid response and a bold or even fierce one.

Located smack-dab in the middle of the brain, these clusters, or nuclei, each send signals to a different area of the brain, igniting opposite behaviors in the face of a visual threat. By selectively altering the activation levels of the two nuclei, the investigators could dispose the mice to freeze or duck into a hiding space, or to aggressively stand their ground, when approached by a simulated predator.

People’s brains probably possess equivalent circuitry, said Andrew Huberman, PhD, associate professor of neurobiology and of ophthalmology. So, finding ways to noninvasively shift the balance between the signaling strengths of the two nuclei in advance of, or in the midst of, situations that people perceive as threatening may help people with excessive anxiety, phobias or post-traumatic stress disorder lead more normal lives.

“This opens the door to future work on how to shift us from paralysis and fear to being able to confront challenges in ways that make our lives better,” said Huberman, the senior author of a paper describing the experimental results. It was published online May 2 in Nature. Graduate student Lindsey Salay is the lead author.

Perilous life of a mouse
There are plenty of real threats in a mouse’s world, and the rodents have evolved to deal with those threats as best they can. For example, they’re innately afraid of aerial predators, such as a hawk or owl swooping down on them. When a mouse in an open field perceives a raptor overhead, it must make a split-second decision to either freeze, making it harder for the predator to detect; duck into a shelter, if one is available; or to run for its life.

To learn how brain activity changes in the face of such a visual threat, Salay simulated a looming predator’s approach using a scenario devised some years ago by neurobiologist Melis Yilmaz Balban, PhD, now a postdoctoral scholar in Huberman’s lab. It involves a chamber about the size of a 20-gallon fish tank, with a video screen covering most of its ceiling. This overhead screen can display an expanding black disc simulating a bird-of-prey’s aerial approach.

Looking for brain regions that were more active in mice exposed to this “looming predator” than in unexposed mice, Salay pinpointed a structure called the ventral midline thalamus, or vMT.

Salay mapped the inputs and outputs of the vMT and found that it receives sensory signals and inputs from regions of the brain that register internal brain states, such as arousal levels. But in contrast to the broad inputs the vMT receives, its output destination points were remarkably selective. The scientists traced these outputs to two main destinations: the basolateral amygdala and the medial prefrontal cortex. Previous work has tied the amygdala to the processing of threat detection and fear, and the medial prefrontal cortex is associated with high-level executive functions and anxiety.

Further inquiry revealed that the nerve tract leading to the basolateral amygdala emanates from a nerve-cell cluster in the vMT called the xiphoid nucleus. The tract that leads to the medial prefrontal cortex, the investigators learned, comes from a cluster called the nucleus reuniens, which snugly envelopes the xiphoid nucleus.

Next, the investigators selectively modified specific sets of nerve cells in mice’s brains so they could stimulate or inhibit signaling in these two nerve tracts. Exclusively stimulating xiphoid activity markedly increased mice’s propensity to freeze in place in the presence of a perceived aerial predator. Exclusively boosting activity in the tract running from the nucleus reuniens to the medial prefrontal cortex in mice exposed to the looming-predator stimulus radically increased a response seldom seen under similar conditions in the wild or in previous open-field experiments: The mice stood their ground, right out in the open, and rattled their tails, an action ordinarily associated with aggression in the species.

Thumping tails

This “courageous” behavior was unmistakable, and loud, Huberman said. “You could hear their tails thumping against the side of the chamber. It’s the mouse equivalent of slapping and beating your chest and saying, ‘OK, let’s fight!’” The mice in which the nucleus reuniens was stimulated also ran around more in the chamber’s open area, as opposed to simply running toward hiding places. But it wasn’t because nucleus reuniens stimulation put ants in their pants; in the absence of a simulated looming predator, the same mice just chilled out.

In another experiment, the researchers showed that stimulating mice’s nucleus reuniens for 30 seconds before displaying the “looming predator” induced the same increase in tail rattling and running around in the unprotected part of the chamber as did vMT stimulation executed concurrently with the display. This suggests, Huberman said, that stimulating nerve cells leading from the nucleus reunions to the prefrontal cortex induces a shift in the brain’s internal state, predisposing mice to act more boldly.

Another experiment pinpointed the likely nature of that internal-state shift: arousal of the autonomic nervous system, which kick-starts the fight, flight or freeze response. Stimulating either the vMT as a whole or just the nucleus reuniens increased the mice’s pupil diameter — a good proxy of autonomic arousal.

On repeated exposures to the looming-predator mockup, the mice became habituated. Their spontaneous vMT firing diminished, as did their behavioral responses. This correlates with lowered autonomic arousal levels.

Human brains harbor a structure equivalent to the vMT, Huberman said. He speculated that in people with phobias, constant anxiety or PTSD, malfunctioning circuitry or traumatic episodes may prevent vMT signaling from dropping off with repeated exposure to a stress-inducing situation. In other experiments, his group is now exploring the efficacy of techniques, such as deep breathing and relaxation of visual fixation, in adjusting the arousal states of people suffering from these problems. The thinking is that reducing vMT signaling in such individuals, or altering the balance of signaling strength from their human equivalents of the xiphoid nucleus and nucleus reuniens may increase their flexibility in coping with stress.

Reference:
Salay, L. D., Ishiko, N., & Huberman, A. D. (2018). A midline thalamic circuit determines reactions to visual threat. Nature. doi:10.1038/s41586-018-0078-2

http://med.stanford.edu/news/all-news/2018/05/scientists-find-fear-courage-switches-in-brain.html


The study simulated long-term consumption of three cups of coffee a day.

It is well known that memory problems are the hallmarks of Alzheimer’s disease. However, this dementia is also characterized by neuro-psychiatric symptoms, which may be strongly present already in the first stages of the disorder. Known as Behavioural and Psychological Symptoms of Dementia (BPSD), this array of symptoms — including anxiety, apathy, depression, hallucinations, paranoia and sundowning (or late-day confusion) — are manifested in different manners depending on the individual patient, and are considered the strongest source of distress for patients and caregivers.


Coffee and caffeine: good or bad for dementia?

Caffeine has recently been suggested as a strategy to prevent dementia, both in patients with Alzheimer’s disease and in normal ageing processes. This is due to its action in blocking molecules — adenosine receptors — which may cause dysfunctions and diseases in old age. However, there is some evidence that once cognitive and neuro-psychiatric symptoms develop, caffeine may exert opposite effects.

To investigate this further, researchers from Spain and Sweden conducted a study with normal ageing mice and familial Alzheimer’s models. The research, published in Frontiers in Pharmacology, was conducted from the onset of the disease up to more advanced stages, as well as in healthy age-matched mice.

“The mice develop Alzheimer’s disease in a very close manner to human patients with early-onset form of the disease,” explains first author Raquel Baeta-Corral, from Universitat Autònoma de Barcelona, Spain. “They not only exhibit the typical cognitive problems but also a number of BPSD-like symptoms. This makes them a valuable model to address whether the benefits of caffeine will be able to compensate its putative negative effects.”

“We had previously demonstrated the importance of the adenosine A1 receptor as the cause of some of caffeine’s adverse effects,” explains Dr. Björn Johansson, a researcher and physician at the Karolinska University Hospital, Sweden.

“In this study, we simulated a long oral treatment with a very low dose of caffeine (0.3 mg/mL) — equivalent to three cups of coffee a day for a human — to answer a question which is relevant for patients with Alzheimer’s, but also for the ageing population in general, and that in people would take years to be solved since we would need to wait until the patients were aged.”

Worsened Alzheimer’s symptoms outweigh cognition benefits

The results indicate that caffeine alters the behavior of healthy mice and worsens the neuropsychiatric symptoms of mice with Alzheimer’s disease. The researchers discovered significant effects in the majority of the study variables — and especially in relation to neophobia (a fear of everything new), anxiety-related behaviors, and emotional and cognitive flexibility.

In mice with Alzheimer’s disease, the increase in neophobia and anxiety-related behaviours exacerbates their BPSD-like profile. Learning and memory, strongly influenced by anxiety, got little benefit from caffeine.

“Our observations of adverse caffeine effects in an Alzheimer’s disease model, together with previous clinical observations, suggest that an exacerbation of BPSD-like symptoms may partly interfere with the beneficial cognitive effects of caffeine. These results are relevant when coffee-derived new potential treatments for dementia are to be devised and tested,” says Dr. Lydia Giménez-Llort, researcher from the INc-UAB Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, and lead researcher of the project.

The results of the study form part of the PhD thesis of Raquel Baeta-Corral, first author of the article, and are the product of a research led by Lydia Giménez-Llort, Director of the Medical Psychology Unit, Department of Psychiatry and Legal Medicine and researcher at the UAB Institute of Neuroscience, together with Dr Björn Johansson, Researcher at the Department of Molecular Medicine and Surgery, Karolinska Institutet and the Department of Geriatrics, Karolinska University Hospital, Sweden, under the framework of the Health Research Fund project of the Institute of Health Carlos III.

Long-term caffeine worsens symptoms associated with Alzheimer’s disease

by Bryan Nelson

Mice are known for their squeaks, but scientists have just discovered how these diminutive rodents are also capable of making ultrasonic vocalizations far beyond the human capacity to hear. And the secret songs they sing usually take the form of love ballads for their mates.

Though researchers have known for a while that a fair amount of mouse communication happens at ultrasonic frequencies, they’ve only just figured out how the rodents do it. Using ultra-high-speed video recording at a whopping 100,000 frames per second, the team was able to see that a mouse is capable of pointing a small air jet, which comes from the windpipe, to blow against the inner wall of the larynx. This causes a resonance and produces an ultrasonic whistle.

“Mice make ultrasound in a way never found before in any animal,” said study lead author Elena Mahrt, from Washington State University, in a press release.

The mechanism is so bizarre that its closest analogue might be in human technology. Namely, what’s happening in the throats of mice is akin to a jet engine.

“This mechanism is known only to produce sound in supersonic flow applications, such as vertical takeoff and landing with jet engines, or high-speed subsonic flows, such as jets for rapid cooling of electrical components and turbines,” said study co-author Dr. Anurag Agarwal. “Mice seem to be doing something very complicated and clever to make ultrasound.”

Humans can’t hear these sounds, and maybe that’s the point. Singing in ultrasound allows mice to communicate at frequencies that many other animals can’t hear. That’s a boon when you’re often on the menu for most other larger predators.

Scientists think that the ultrasound whistles are actually mating calls, often sung by males to attract females; a mouse version of a “cat call,” perhaps. The sounds are also likely used for signaling territorial boundaries to rivals, though the full extent and use of the songs is still being studied. It’s even possible that this ultrasound mechanism was a prerequisite for the echolocation abilities seen in bats.

“Even though mice have been studied so intensely, they still have some cool tricks up their sleeves,” said senior author Dr. Coen Elemans.

http://www.mnn.com/earth-matters/animals/stories/mice-sing-secret-ultrasonic-frequencies-their-mates