brain and mind–recent discoveries...11/7/2018 1 brain and mind–recent discoveries sanjay p....
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Brain and Mind–Recent Discoveries
Sanjay P. Singh, MD, FAANChairman & Professor,
Department of Neurology,Creighton University School of Medicine.
Director – Neurological Institute, CHI Health
Brain and Mind–Recent Discoveries
• Journey through time
• Journey through a lifetime
• Journey of discovery
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Humans have a larger Brain
NOTCH2NL – Enlarged Brain
• A cluster of genes found only in humans might have had a key role in the evolution of the unusually bulky Homo sapiens brain.
• Found that members of a gene family called NOTCH2NL are active in humans — but not in apes.
• The researchers say that the genes arose in their current form roughly 3–4 million years ago, after the human lineage split from the branch that led to the great apes.
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• Human NOTCH2NL gene delays the specialization of stem cells so they have a chance to produce many more copies of themselves and therefore many more neurons when they specialize.
NOTCH2NL ‐ Brain
• When the team deleted the genes from human brains growing in lab dishes, the resulting organs were smaller than controls that had normal NOTCH2NL gene activity.
• Found that NOTCH2NL genes are active in progenitor cells that give rise to neurons.
• This suggests that NOTCH2NL helps to drive the enlargement of the brain during fetal development.
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Humans have Language
Neuroscientists identify key role of language gene
• Neuroscientists have found that a gene mutation that arose more than half a million years ago may be key to humans’ unique ability to produce and understand speech.
• Researchers from MIT and several European universities have shown that the human version of a gene called Foxp2 makes it easier to transform new experiences into routine procedures.
• When they engineered mice to express humanized Foxp2, the mice learned to run a maze much more quickly than normal mice.
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Neuroscientists identify key role of language gene
• Foxp2 may help humans with a key component of learning language — transforming experiences, such as hearing the word “glass” when we are shown a glass of water, into a nearly automatic association of that word with objects that look and function like glasses.
• All animal species communicate with each other, but humans have a unique ability to generate and comprehend language.
Neuroscientists identify key role of language gene
• The gene was first identified in a group of family members who had severe difficulties in speaking and understanding speech, and who were found to carry a mutated version of the Foxp2 gene.
• Human Foxp2 gene bestows longer dendrites —the slender extensions that neurons use to communicate with each other — in the striatum, a part of the brain implicated in habit formation. They were also better at forming new synapses, or connections between neurons.
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Neuroscientists identify key role of language gene ‐ EVOLUTION
• Mutations in the FOXP2 gene could help explain why humans can speak but chimps can't.
• Two tiny changes in the sequence of one gene could have helped install the mechanisms of speech and language in humans.
• Human gene differs from non‐human primates by the substitution of two amino acids, threonine to asparagine substitution at position 303 (T303N) and asparagine to serine substitution at position 325 (N325S). In mice it differs from that of humans by three substitutions, and in zebra finchby seven amino acids
Booba & Keekee – ‘Language’
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Hand and Mouth
• Charles Darwin – scissors – jaw clenching
• Diminutive, teeny weenie, little
• Large, Big
• Gestural communication in our ancestors
• Then your mouth and tongue mimic your hand gestures
• ‘Protolanguage’
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“Brain in a Dish”
Cerebral Organoids
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Cerebral Organoids
• Organoids are three‐dimensional biological structures grown in vitro from different kinds of stem cells that self organise mimicking real organs with organ‐specific cell types.
• The complexity of the human brain has made it difficult to study many brain disorders in model organisms, highlighting the need for an in vitromodel of human brain development.
Cerebral Organoids model
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Cerebral Organoid
An organoid as an in vitro 3D cellular cluster derived from primary tissue (lineage‐restricted adult stem cells), embryonic stem cells (ESCs), or induced pluripotent stem cells (iPSCs), capable of self‐renewal and self‐organization, and exhibiting similar organ functionality as the tissue of origin.
Cerebral Organoids – Fortuitous• The breakthrough in creating these organoidshappened as part of a side project.
• Other researchers had grown neurons in a dish before, and like them, Madeline Lancaster(Vienna) started by using a flat plate to “play” with neural stem cells—the kind that form into neurons and other cells in the nervous system.
• Sometimes, she says, “I’d get neural stem cells that wouldn’t really stay in 2‐D, and they would kind of fall off the plate and they’d make 3‐D clumps—and rather than ignoring them or throwing them away, I thought, ‘Those are cool—let’s see what happens if I let them keep growing.’”
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Cerebral Organoids ‐ Fortuitous
• But there was a major challenge: how to keep the tissue at the center of the organoids fed without the benefit of veins. Lancaster’s solution was to encapsulate each organoid in a matrix known to nurture cells, put a dozen of these blobs in a nutritious bath, and shake or spin it all to keep the organoids awash in cellular food.
Cerebral Organoids model human brain development
• Scientists have developed a human pluripotent stem cell‐derived three‐dimensional organoidculture system, termed cerebral organoids, that develop various discrete, although interdependent, brain regions. These include a cerebral cortex.
• The fully grown organoid is comparable to a 9‐week‐old fetal brain.
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Cerebral Organoids
• The ‘mini brain’ models, developed by Thomas Hartung’s group (Johns Hopkins University, Baltimore MD) can spontaneous generate electrical activity, producing brain waves.
• And because these mini‐brains can be grown from a specific person’s cells, organoids could serve as unprecedentedly accurate models for a wide range of diseases.
• What goes wrong, for example, in neurons derived directly from someone with Alzheimer’s disease?
Cerebral Organoids
• Researchers such as Rudolph Jaenisch at MIT and Guo‐li Ming at Johns Hopkins are beginning to use brain organoids to investigate autism, schizophrenia, and epilepsy.
• What makes cerebral organoids particularly useful is that their growth mirrors aspects of human brain development. The cells divide, take on the characteristics of, say, the cerebellum, cluster together in layers, and start to look like the discrete three‐dimensional structures of a brain.
• If something goes wrong along the way—which is observable as the organoids grow—scientists can look for potential causes, mechanisms, and even drug treatments.
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Microcephaly
• Cerebral Organoids – from Microcephaly patient.
• Demonstrated premature neuronal differentiation in patient organoids and then a premature cessation of this function. A defect that could help to explain the disease phenotype.
Lancaster et al. Nature volume 501, pages 373–379 (19 September 2013)
Organoid generation from human pluripotent stem cells.
19 SEPTEMBER 2013 | VOL 501 | NATURE
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Models to study Brain Development
• While mice may fall short in terms of modeling certain features of human cortical development, ferrets are proving to provide an attractive alternative.
• Ferrets not only have cortical surface morphologies more similar to humans, but also a larger cortex and a higher diversity of neural progenitors, studies of gene function during neurogenesis in ferrets seem to more accurately reflect their potential functions in humans.
Models to study Brain Development
• An interesting example of this comes from a new study from Walsh, Bae, and colleagues (Johnson et al.,2018).
• By disrupting in ferrets a gene called ASPM—a very common recessive microcephaly gene whose disruption in mice has little consequence—they not only recapitulated the severe microcephaly seen in humans, but could also pinpoint the neurodevelopmental dysfunction to a premature movement of a population of neural progenitor cells that are absent in mice.
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Microcephaly
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Microcephaly – ASPM gene
Ponting et al. Current Opinion in Genetics & Development; Volume 15, Issue 3, June 2005, Pages 241‐248
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SLEEP & Brain Washing
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“Brainwashing” – Glymphatic System
Sleep Drives Metabolite Clearance from the Adult Brain. – L. Xie, M. Nedergaard et al.
Science 18 October 2013: Vol. 342 no. 6156 pp. 373-377
When mice sleep, fluid‐filled channels (pale blue) between neurons expand and flush out waste.
SLEEP - “Brainwashing”
Sleep Drives Metabolite Clearance from the Adult Brain. – L. Xie, M. Nedergaard et al.Science 18 October 2013: Vol. 342 no. 6156 pp. 373‐377
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“Brainwashing”
• “Glymphatic System”
• A network of microscopic, fluid-filled channels that clears toxins from the brain, much as the lymphatic system clears out metabolic waste products from the rest of the body.
• Instead of carrying lymph, this system transports waste-laden cerebrospinal fluid (CSF).
“Brainwashing” – Glymphatic System
• Glia, the brain’s non-neuronal cells, control the flow of CSF through channels in their cell membranes. “If we delete the channels in glial cells, the flow almost stops.”
• A comparison of the volume of space between nerve cells while the mice were awake and asleep revealed that the glial channels carrying CSF expanded by 60% when the mice were asleep.
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Volume Variation. • The extracellular
(interstitial) space in the cortex of the mouse brain, through which cerebral spinal fluid moves, increases from 14% in the awake animal to 23% in the sleeping animal, an increase that allows the faster clearance of metabolic waste products and toxins. Therapeutics could potentially exploit this
dynamic to clear factors associated with conditions such as epilepsy, migraines, and insomnia.
“Brainwashing” - Glymphatic System
• Injected labeled β amyloid proteins into the brains of sleeping mice and awake mice and found that during sleep, CSF cleared away this “dirt” outside of the cells twice as quickly—“like a dishwasher”.
• Such proteins can aggregate as pathogenic plaques outside cells and are associated with Alzheimer’s disease.
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“Brainwashing” - Glymphatic System
• Many neurological diseases — from Alzheimer’s disease to Stroke and Dementia— are associated with sleep disturbances.
• Study suggests that lack of sleep could have a causal role, by allowing the byproducts to build up and cause brain damage.
Sleep Drives Metabolite Clearance from the Adult Brain. – L. Xie, M. Nedergaard et al.Science 18 October 2013: Vol. 342 no. 6156 pp. 373‐377
LYMPHATIC WASTE DISPOSAL IN THE BRAIN
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Lymphatic waste disposal in the Brain
• This meningeal lymphatic system was first found2 in 1787 and has been ‘rediscovered’ this decade.
• The brain does not have its own lymphatic vessels to manage the clearance of waste.
• Proteins and waste are transported from the brain’s interstitial fluid (ISF) along blood‐vessel walls to reach the cerebrospinal fluid (CSF) in a space within the meninges.
• Lymphatic vessels in the meninges drain CSF and ISF containing waste products.
Nature 560, 172‐174 (2018)
Lymphatic waste disposal in the Brain
• During ageing, both vessel systems can become impaired – Lymphatic & blood vessel.
• The diameter of the meningeal lymphatic vessels decreases, causing decreased waste clearance by this route.
• This defect, along with impaired clearance by blood vessels, leads to Aβ accumulation in the brain.
Nature 560, 172‐174 (2018)
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Lymphatic waste disposal in the Brain
The Seventh Sense – Immune System
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Seventh sense – Immune System
• Sight, hearing, touch, taste, smell, body awareness (formally, proprioception): six of the widely recognized senses in our bodies that help tell us about the world around us.
• The immune system may “qualify as a kind of surveillance organ that detects microorganisms in ... the body and informs the brain about them, much as our eyes relay visual information and our ears transmit auditory signals.”
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The Brain Immune Connection
• Mice lacking in Adaptive immunity showed not only impaired spatial learning behavior but also compromised social behavior.
• PTSD – in the mouse model incidence is 7 times higher in mice without adaptive immunity.
Brain, Belief & Immunity
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Using Pavlov’s Theory
Conditioned Immunosuppression
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Behaviorally Conditioned Immunosuppression in Humans
Clinical Relevance
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Being Happy can Cure Cancer?
• Activating the reward system boosts anti‐tumor immunity in mice.
• From savoring a piece of cake to hugging a friend, many of life’s pleasures trigger a similar reaction in the brain—a surge of chemicals that tell the body “that was good, do it again.”
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Nature Communications volume 9, Article number: 2723: (July 2018)
The Reward Pathway
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Could Brain Stimulation Slow Cancer?
• The brain’s reward system, specifically the dopaminergic neurons in the ventral tegmental area (VTA), constitutes a key neuronal network whose activation mediates positive emotions, expectations, and motivation.
• The dopaminergic projections from the VTA to components of the limbic system are causally associated with motivated behavior and reward perception.
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Being Happy can Cure Cancer?
• Pharmacological studies indicated a connection between reward system activity and immune modulation, and it was recently shown that reward system activity can boost antibacterial immunity.
• The immune system can also act as a double‐edged sword. On the one hand, it generates effector cells, such as CD8 T cells and NK cells that can eliminate tumors.
• On the other hand, some immune cell subsets, such as myeloid derived suppressor cells (MDSCs), act to support tumor growth by suppressing the anti‐tumor immune response and by generating a favorable environment for the tumor.
“It’s like doing immunotherapy without Medication”
• Activating the brain’s reward system unleashes chemical signals that thwart this web of checks and balances in a manner that disables these pro‐tumor MDSCs. That, in turn, allows typical anti‐tumor immune responses to proceed.
• In mice with implanted cancer cells, two weeks of daily reward circuit stimulation produced a powerful response—their tumors were 40 to 50 percent smaller than those in control mice that didn’t get the brain activation.
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Evolution of Civilizations & Societies.
Mirror Neurons !!!!
Giacomo Rizzolatti
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“MIRROR NEURONS and imitation learning as the driving force behind "the great leap forward" in human evolution”
The hominid brain reached almost its present size —and perhaps even its present “intellectual” capacity about 250,000 years ago .
Mirror Neurons
• Mirror neurons, a small circuit of cells in the premotor cortex and inferior parietal cortex.
• What makes these cells so interesting is that they are activated both when we perform a certain action—such as smiling or reaching for a cup—and when we observe someone else performing that same action.
• In other words, they collapse the distinction between seeing and doing.
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Mirror Neurons
• Mirror neurons are the only brain cells we know of that seem specialized to code the actions of other people and also our own actions.
• They are obviously essential brain cells for social interactions. Without them, we would likely be blind to the actions, intentions and emotions of other people.
Mirror Neurons
• The way mirror neurons likely let us understand others is by providing some kind of inner imitation of the actions of other people, which in turn leads us to “simulate” the intentions and emotions associated with those actions.
• When I see you smiling, my mirror neurons for smiling fire up, too, initiating a cascade of neural activity that evokes the feeling we typically associate with a smile. I don’t need to make any inference on what you are feeling, I experience immediately and effortlessly (in a milder form, of course) what you are experiencing.
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Mirror Neurons
Half the mirror neurons got activated when an action is witnessed within your reach and the other half get activated when the action is at a distance.
Degree of activation of mirror neurons is somewhat related with familiarity. Autistic.
Self ‐ family ‐ stranger
Neuroscience 2007 Peter Thier, PhD, at Tübingen University,
Oberman et al.
Key regions (large sphere) and subregions (small sphere) of the mirror neuron system. The image on the left is lateral view of left hemisphere and that on the right is top view of both hemispheres.
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Autism – Thinning of mirror neurons
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Autism & Mirror Neurons• Patients with autism have hard time understanding the mental states of
other people; this is why social interactions are not easy for these patients. Reduced mirror neuron activity obviously weakens the ability of these patients to experience immediately and effortlessly what other people are experiencing, thus making social interactions difficult .
• Patients with autism have also often motor problems and language problems. It turns out that a deficit in mirror neurons can in principle explain also these other major symptoms.
• The motor deficits in autism can be easily explained because mirror neurons are just special types of premotor neurons, brain cells essential for planning and selecting actions.
• It has been also hypothesized that mirror neurons may be important in language evolution and language acquisition. Indeed, a human brain area that likely contains mirror neurons overlaps with a major language area, the so‐called Broca’s area.
• Thus, a deficit in mirror neurons can in principle account for three major symptoms of autism, the social, motor and language problems.
Mirror neuron activity predicts people's decision‐making in moral dilemmas
• Researchers found that the brain's inferior frontal cortex (circled) is more active in people who are more averse to harming others when facing moral dilemmas.
2018. UCLA Health
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Unique Personalities & Responses
Same situation Different response
Synapse Dropout.‐ “pruning”
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“Synesthesia”
• Five is green, two is red !
• C – sharp is red !
• Francis Galton 19th century
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