ORCA 6th Annual Art and Science of Animal Training Conference Dr. Jaak Panksepp

Well good morning. HOpefully you have had a quick breakfast and plenty of coffee. I will be talking about feelings and animals. How many people believe that animals have emotional feelings? Well then I'm talking to the converted. But of course this is not a matter of belief but it is also a matter of science and evidence and I will try to give you the argument that the science supports that a variety of basic emotional feelings built into the brain and its capacities for living effectively in the world. There's this dilemma from Freud.. that says that there's an impenetrable mystery of experieces.

Usually in the academy people are told not to go there because you can't go there. A scientific argument has to be based on evidence and that is what I will try to share with you today. Here is a painting that a friend did for me a couple of years ago. Even chickens have feelings and we don't know how far back it goes in evolution but it must go way back because they are tools for living. They tell the animal whether they are going to survive or whether they are in a terrible place where they may not survive. The feeling of pain tells them to stay off your injured limb, or else it will take you out of action.

Human children are sometimes born without the capacity to feel pain and they all die prematurely because they don't know how to protect themselves. Feelings allow the brain to protect itself. All the good feelings tell the animal to have more of those because it promotes survival. So I will be talking about primary processes. We talked about this yesterday. But I will be talking about the things that evolution gave animals for living. They are primary processes and they control everything in the brain and mind. If the feeling systems are taken away, the mind collapses and animals become unconscious.

Most of the work in the academy has been done on secondary processes like memory. These distribute feelings into the world. Wehn we born, we have very little... very small top mind or cognitive mind that is created by how you live in a world, how you interact and how you.. what you learn by yourself or from others. So the dillema that we're facing is that we need different words for these different levels and I will capitalize the primary emotions because that's a special scientific term for neural networks that exist in the brain. The PANIC system. That's very important. If the animal gets distressed when you leave, they are feeling separation distress and there are ways now to modulate it now from puppy prozac to a future of many other things like taking these feelings seriously. In the 1960s we started to map these systems. In the late 1960s.

The mid level might need another name. Like maybe grief would be approopriate. We don't have specific circuits because that comes from learning. You're sad because you're missing a specific person. The panic can occur from missing a specific person just being alone when you're helpless. TSo there's this mess with complex words with very little agreement. That's why I capitalized so that we can ignore the neurological fallacies, that you're confusing the complex whole for just the part. In these there are speical terms.

Pre-clinical affective neuroscience modeling of depression & evaluation of three new antidepressant strategies

We are all mammals or brothers and sisters and share the same basic mechanisms. In veterinary college we learn more about human bodies by studying animal bodies. WE will learn more about the human mind by studying the mind of animal minds. The detailed scientific methods might be controversial but those are the paths to knowledge.

We have these ancient minds inside our own minds. We share mechanisms of anger, sexual lust, maternal care, desire, separation distress, playfulness, there are networks in the brain that mediate these processes. I wrote this second large book for clinicians ("The archaeology of the mind"). I moved to neuroscience because there was no conversations about emotions or emotional feelings in animals. So I decided to try to make a science of it. It's not very popular to talk about the minds of animals. The rigorous scientists say that we can't go to the mind of the animal. I agree that we can't penetrate their thoughts yet; that's mind reading and an art rather than a science.

But with regards to feelings, there is a science to that if you have the skills to pursue, or either falsify or disagree or either confirm and agree. I will be talking about things that will probably have a lot of agreement if there were people working in the field. Most people studying animal emotional learning they are studying learning. They are studying pavlovian learning. Freezing, flight, pooping, autonomic changes, an animal gets, neutral stimulus. But these folks do not say that the naimal experience fears because that would be mind reading.

When we want to understand the feelings of other animals, we want to understand emotions. Animal lovers are convinced that animals have feelings. Most scientists are skeptical. A famous air conditioner at New York University wrote a paper in 2012 and said that we will never know what animals feel. That's the prevailing bias. The 100 years that .. we don't try to go to that level. We can go to that level because feelings evolved. They are tools for living. WThey are natural parts of our minds. They always feel good or bad. They are valiance. We can ask animals whether, when a certain emotional system is activated by certain behavioral changes, is it neutral, does it matter, does it feel good, is it reward, or does it feel bad as a punishment? It's a simple argument.

There's a lot of psychology.. whenever you activate an emotional system it will always be rewarding or punishing in a sensible ways. They can tell us if they have good feelings or bad feelings. If we understand their basic feelings, we will begin to understand our own. So what the heck are we waiting for? Well these guys are the majority, so the majority rules in the conversation. I am trying to change the conversation and I hope that you can be part of it.

This was a picture from Discover Magazine that covered my work. The April issue of Discover has "Freud returns" and there's an article about my friend who is a psychoanalyst and a neuroscientist... "Freud is the last guy who talked about".. there is now a movement that is getting larger and larger in neural psychoanalysis, a kind of clinical discipline that is looking for the basic science of emotional feelings.

You can tickle the brain with little mind.. you can't feel with the most sensitive parts of the body like the tongue. You can activate systems in the brain. When you activate very specific systems and when the.. this anger display was discovered by Walter Hesomething in the 1930s. He was looking for the autonomic nervous system. To his surprise, when he found those areas, the sympathetic nervous system in the brain, the animal would show an emotional response like the anger display. He called it sham rage. He got the Nobel prize in 1940 something for discovering.. he only called it only sham rage, because he didn't want his work to be marginalized by the powerful movement in America. He always believed it though.

In the laboratory rat, the anatomy was the same. When I turn on this anger response on, si it neutral, is it positive or is it punishing? And it turned out that all animals wanted to turn it off. Anger does not feel good. Well, someone might say that, I actually got something when I got angry, well that's not the primary process, that's the consequence of perhaps it works out for you sometimes. So there can be secondary benefits, but as a primary system it is negative because you're fighting for resources from someone that is wanting to take your resources. It's a defense system.

Angry behavior reflects angry feelings. And it does turn out that humans in enural psychiatry have been stimulating these brain areas and they get angry. And they report a deep profound.. they start expressing it in language, and they apologize when the stimulation is turned off.

So the anger system has 3 levels. Hierarchical control of brain stimulation-evoked anger response. You need much more juice. That response is weaker. It depends on lower areas. IN the hypothalamus you can produce it at much lower current levels and it doesn't depend on the amygdala. The amgydala can be gone and the animal can still get angry. But at a lower level youcan turn on the anger response without the hypothalamic or the amygdala. The lower down in the brain you go, the more powerful the emotional respone gets.

We know abunch about the connections and the circuitry. So the argument is simple, but there are chemistries in this circuit that will be targets for human psychiatric issues like excessive anger, which is a big problem, or perhaps problem animals at ... but perhaps give the dogs assisted medication. Emotional CURs with Deep Brain Stimulation (DBS), the states are always rewarding or punishing. It could be used right now clinically.

These are the seven systems that I can defend. There is a seeking system. I spent a lot of time on it yesterday. THis is the system that allows animals to explore and find everything they need for survival. Then there is a rage system to protect your resources, there is a fear system to protect your life because there are predators that want you for a meal. Of course if you are a mammal, you must have a ocmplex reproductive urge, there's lust, and it's slightly different in males and females and different chemistries. Our babies are born immature, so you must have a maternal instinct, there's a care system and it's much more powerful in the female brain. And the hormones of pregnancy activate this system a couple days before the baby is born. And the little one.. our little ones need to show the prents, especially the mother, how important she is. If the little one gets lost, they feel panic, they go into a panic attack and cry, we mapped that system and it does not feel good. Animals like to turn it off. There is a play system in the brain, and we as the most playful culture perhaps in the world, with our professional sport symbolizing playful attitudes, we have not come to terms with that, and our little ones are not getting enough play and that has severe consequences for our culture that has not been discussed yet. Former Governor said.. drive by five.. if you haven't been thriving by 5, then you haven't had a proper upbringing and play is a part of it.

Some of our work on this system has panned out into 3 antidepressant treatments that seem to be working on humans. They are in testing but they are so far testing positive. What are the feelings that these systems generate? Enthusiasm is the feeling generated by the seeking system. When you are dpressed, you don't have enough enthusiasm. And for the rage system, you get pissed off. The fear system generates anxious feelings. Lust- horny. Care- tender and loving. Panci is lonely and sad. Play is joyous. We don't have an antidepressant for social joy. The third is the one to shut down and dampen panic, because psychological pain is the gateway to depression. If you take the animal's pain seriously, you can move along much more rapidly rather than just focusing on behavior.

Each emotion has their own external manifestations. And they are all rewarding or punishing. All the blue one, rage is negative, all the yellow ones are positive. The animal likes to turn them on if given the chance. That's the measure of feelings.

We know a lot about their anatomy and their chemistry, and if you are interested in the details, the first big book I wrote summarizes the details up to 1997. And there's a beginning of ..

Nucleus accum.. mesolimbic and laterla hypothalamus - seeking expectancy system.

If you understand consciousness, it's an ancient function in the brain. Someone in Italy didn't do these horrible studies.. cutting the brain stem at various locations. The upper cut, right through the midbrain, the lights are out, unconscious. When you move the cut a little further back, no more sensory input, just eye movement. And then the animal's brain wakes up. You can interrogate the animal through eye movements. Prior to that you only had olfaction and vision. Consciousness emerges in this area in the lower mid-brain, in the ascending reticular activating system. If you stimulate this system if you're in a coma, you wake up for a while, as long as that area isn't damaged, even in a persistent vegetative state. They are very rich in emotional feelings. That might be the most ancient form of experience.. namely, emotional feelings. Shocking. You can imagine the grand canyon being a metaphor for that, the ret of the brain would be as dry as the desert, and the ascending reticular system, ARAS.. it gives the brain the capacity to be awake and to feel things. That's a fact that has been known for 60-70 years but it hasn't penetrated conversation very much.

So these higher processes depend completely on, the brain stem, the emotional process, the primary process just as a category label. Does this apply to humans? It certainly does. There are children that are born without this part... hydrocephalic.. so they have just a hypothalamus, pretty much the top of the brain is gone. Are these children unconscious? If this happened to any of us, yes. But these children are alive and awake and full of passion and emotions. Here's a child, let me just show you this child's brain. And we wrote a paper on this a couple years ago.

The "id" knows more than the "ego" admits: neuropsycho analytic and primal consciousness perspectives on the interface between affective and cognitive neuroscience

They make choices, affective hoices, and these pictures are used with parental permission. The lower mind is very large in these children. Tha's the primary process. ALl of these emotions go downstream in the most ancient part of the brain called the... if you eliminate the paradactly brain... consciousness is probably built upon feelings that are intrinsic values that need to be distributed in space and time by learning. So there might be a core self there. Some people may even call it a soul. It's the lowest amount of energy to get coherent amount of.. small amounts of brain damage can cause a loss of consciousness. There's the most massive amount of convergence of systems per cubic centimeter of neural tissue. It's very well connected.

This primary process gets very small because of learning and memory and it puts all kinds of ideas on the top of our brain. Most of them factual, some of them try to focus on the facts. There we are with lots of different opinons, rights and wrong, and we can't determine objectively. But all these systems survive. These systems are essential for mental life itself. So we have affective consciousness down there ("primary feelings"). That middle part is the unconscious. The learning and memory part just work uncosnciousnyl. We see the consequences but not the mechanism in action. And on top we have cognitive consciousness that depends on affective consciousness. The lower part is not aware. You don't know.. you don't know that you're experiencing, you're just experiencing. That's called qualia philosophically.. pure experience that we share with other animals.That is a remarkable responsibility that we have as a consequence  So what happenn depression. It's taken for a spin, okay? Psychological pain, the panic system, is a fun little term for the sad poet in our brain.

The purple on top of the cortex are indicating the..

Damasio, et al. (2000) Nature Neuroscience, 3: 1049-1056

The reds and yellows are arousal. They are exactly the areas of arousal. We don't feel them on the top of the brain. On the top we have.. grief and sadness system that we mapped. The separation call in infant chicken and guinnea pig, and it was the same in birds and mammals. On the right, we had happy feelings, in subcortical areas, a very diffuse system. When we mapped animal joy, namely rat laughter, and yes there is rat laughter that is exhibited during play, animals love to turn that on if given the chance. That is missing in depressed people. We look for molecules that facilitate. Poppy is a very powerful reducer of physical but also psychological pain. Psychological pain is a gateway to depression and suicide. Some people try to take away that pain by killing themselves.

When we mapped the guinnea pig in the 70s, we got the picture in the lower left. Damasio when he imaged humans he got a very similar picture. Here's just a summary of 20 or 30 years of work. Opiods were suppressors of these systems. When you pet chickens, when you hold them they are releasing opiods and they are in comfort. Next we found a molecule that mediates maternal behavior, it's very effective at suppressing crying... oxytocin (1980s). The chemistry of motehrhood are the chemistries of care. What other chemistry is required? Well, prolactin. It is a very effective molecule for reducing psychological pain (1990s). These are pretty big ones.

So the opium poppy... people get addicted to this molecule very easily. They get addicted usually because of too much psychological pain, and a molecule regulates it, and we put these people in jail as opposed to mandated treatments. Social bonding and attachment. The feeling that you have if you're an opium addict is very similar to the child lost in the woods crying out in pain. So it's amazing that this addictive process is one of the most cherished values in our society, and the people who use the molecule to control their own psychological pain are made criminals in our system and we put them in jail instead of mandated therapy.

Tiny doses can reduce the separation call. The separation call is the most sensitive response that anyone has ever found that opiods modify. And we demonstrate the internal opiods do the same thing, that's a long story. Dogs were the first one we found, and we thought that we would study social bonding but this was too early in the 70s. So we went to guinnea pigs, and we did deep brain stimulation to map this system, and then we went to chickens, and w e mapped the anatomy and they were the same and there was the same chemistry. These are important for animal trainers to understand what their pets are really feeling. Sorry I can't say a word, but they are probably thinking about their feelings just like we are. The food that tastes good is probably ... so they mask nutrients and taste so they don't necessarily go together.

If you hold a little one and it is crying, it will stop crying immediately. It relaxes and closes it eyes. The hands are releasing opiods in the brain. Have you heard of placebo effects. Occassionally they just give you a placebo or sugar pill and it makes you feel better. So they have an attitude of care or empathy, the release of opiods is an antidepressant. A lot of depressed people can get addicted very easily. Touch alleviates pain oth physical and psychological pain.

The affective neuroscience strategy for understanding affective and.. something. 30 minutes? Good, I thought I was going too slowly.

So it turns out that there is a safe opiod. Buprenorphine (0.2-0.8 mg). It's safe because you can't kill yourself. It only tickles the opiod system. At the high doses it starts balking it. You can't go to respiratory depression, that will kill you. Yoram Yovell et all. It is sometimes used in cancer therapeutics, there was a patch that came out, and we tried it on depressed people and now they are feeling much more normal for really tiny tiny doses.

We have also taken the enthusiasm system. Brain pacemakers have become very popular ever since we've realized that parkinson's disease, the uncontrollable tremeor can be stabilized by a pacemaker in the subthalamic nucleus. I convinced some colleagues in Germany to.. they were psychiatric hospital, a neurosurgeon, T. Schlaepfer, V. Coenen, that perhaps targetting the heart of the seeking system that generates enthusiasm and put a pacemaker. So they just published 7 patients that were treatment resented... they became normalized within a day. THis will be a long time before this becomes standard medicine. They are finishing another 7 right now.

There's a drug development group, it was working on brain cancers and a depression program there. They had technologies there that... we started with GLYX-13 for joy pathways in the brain. Maybe depressed people can't experience social joy or laugh regularly, well maybe we can get knowledge about that system and simulate the capacity for social joy without an addictive molecule.

These three treatments for depression whether you are human or animal will be the same. We had to take.. to Israel. We could not carry the outlet study in this country. It was a demonized drug (buprenorphine). It just didn't work after lots of paperwork.. the opiod system is all over the brain. Panskepp & Bishop 1981. The list of things it doesn't control is a very short list.

Safe opiods are much underutilized in modern psychology. Maybe it helps alleviate psychic pain. There is no medication for suicide. Animals don't do that in that way. But humans do. So I contacted a friend, Yoram Yovell, Low doe and Buprehenoprhine and Suicide (Israel) (2014). Can we test it for suicide? I was able to get him funding for it, and a project is completed after 4 very difficult years. There's a lot of kickback even in Israel. We don't have any medicines for suicide.. and the suggestion that an opiod would take away the psychological pain, well doctors would consider that unacceptable to use opiods in psychology.

This is a safe opiod. I don't want to share this data pubplically before it's published. Pilot data (n=4) with beck suicide inventory (n=60 in ongoing DB-PC study). here's the first four. After even placebo, people felt better, less depressed, this is the Beck Suicide INventory, how many suicidal thoughts do yo uhave. They were both the same, but placebos release opiods, that's hwo the placebo works. By the second week, the placebo effect disappeared but the buprenophine effect was getting larger and that pattern held.

It is a very simple theory. We are modeling psychiatric disorders around feeling systems instead ofj ust behavioral systems. Most people are just focused on behavior. Put an animal in a puddle of water and how long does it swim? That is not the most effective way to go because that changes everything in the brain. We don't know what we're doing; people produce depression by really stressing the heck out of rats and mice. Just terrible stressors. That's too many things in the brain. You have to focus on the emotional systems. We take an affective iew...

So here's another one with deep brain stimulation. These are nested. We are seeking on the primary seeking urge, it doesn't mediate pleasure of sensation, it mediates enthusiasm for life. That's what you need when you're chasing resources. You have to be eager. You have to go for it. If you don't have enough of that, you're psychically depleted, at a higher level there, some people call it "wanting" but it's after you've earned what you need, then you want an object. And wanting is a secondary term.. and up there people might call it something else. So in a depressed person, if they really need more enthusiasm, this is the seeking system.

Medial forebrain bundle Le Gros Clark (1938). It's enormous. Wehn you stimulate this system, animals get very excited and if there's no food they are okay they keep going. If you let them press a lever and they keep going, they will keep pressing the lever for 24 hours, it collapses in exhaustion and then repeats the lever pressing. This system is addicted. The psychostimulatns like cocaine and amphetamine directly effect the seeking system. There's a real problem in elevating this, but the psychological pain dampends this sysstem down. So if every medication has failed, maybe deep brain stimulation will work. If you lesion this system, you have a deep profound untreatable depression. If you stimulate maybe you can get around it.

This is just some little interesting data. Theschedules of reinforcement. This is what Skinner developed to understand animal learning for food. The most interesting one is the fixed interval because these are lever presses. And the animal has to press the lever once a minute in order to get food and the animal is always optimistic and starts pressing in 10 seconds or 20 seconds and it starts going and going. Then it relaxes for a while and it goes on. This system in a rat also activates sniffing, even if the animal is under surgical anaesthesia. Even if it is knocked out, it sniffs. If you get the sniff, you get rewarded, you don't need a road map. What if we just stimulate this system every 20 seconds on a fixed interval schedule?

Spontaneous sniffing patterns come to resemble fixed-interval responding during predictable stimulation of the "seeking system".

It just gets excited the whole time. Very enthusiastic, about nothing. It naturally develops into a shaped scallop.. even though the animal doesn't have to do anything, it spontaneously learns. It learns without the learning having to do any functional effect on the world. That's rather amazing. Then 30 or 40 years later we found rat laughter that happens during play and guess what? It mapped on to the seeking system, but only parts of it. So now we can produce a chirp with brain stimulation. Every place that we produce a chirp, the animal will produce a chirp. We had markers with anesthesia that we could track that system. So what happens when we put an animal, actually pressing a lever to get food. Doe the sniffing system getinto action? And here's the sniffing with respect to the first lever press. 1 second before the first lever press, the sniffing system is already aroused. So we have now read the animal's minds. They have become enthusiastic a second before the behavior. Wow.

So again, this separation distress, that causes depression that can lead to suicide, we have buprenoprhine as a medication. What about a person who has lost enthusiasm for life, still has this system, can we tickle it and make the person feel more normal? Or are we just producing a pleasure response like an orgasm or an ice cream cone on the tongue. Well we think it mediates social joy, and that's what's missing in a lot of depressed people. So let's just focus on the human stody.

If we stimulate the separation system in animals, we dampen the sensitivty of the sequence system. We are modeling the emotional dynamics in the brain, and not just behavior that we can't read accurately. So my colleagues in Germany did a diffusion imaging study..

Cross-species affective functions of the medial forebrain bundle- Implications for the treatment of affective pain and dpression in humans

They use that knowledge to guide... very very large robust systems. This diffusion tensor imaging allows us to map the networks in the brain in vivo and in people using these magnetics fMRI scanners. So the theory is that too much of this system will suppress the seeking system. And when that happens, disphoria and depression begin to emerge. So the aim is to facilitate the seeking system perhaps with deep brain stimulation. Rat play and tickling rats gave us a molecule for safely facilitating the capacity for social joy, but first the brain stimulation.

Schaleaperfer, Coenen, 2013 Rapid effects of deep brain stimulation for treatment-resistant major depression.

Nobody had an orgasm. Nobody said, oh I feel like someone is touch machine is giving me a good massage. They just made plans for the future. When the brain's pacemaker, was just, just map how they organize and identify what place to put the electrodes. These are people who have gone through every available therapy, so they are rather eager to be volunteers for anything that might help. There were 7 people. These are the cumulative individual curves. Six of the seven responded. One did not; unilaterla leectrode, bilateral stimulation did not work. And finally the third one comes from rat play.

When we study rat play, we hear sounds in the ultrasonic range way outside our hearing range. Whenever we tickle these laughter sounds, then the animals self-stimulate. If you have never seen rat play or rat laughter, let's see if I have battery power to do this. (video of rats running into each other). Rob, they're not fighting, they are playing. Play is built into mammalian brains because it allows you to get socialized in a positive, joyful way.

So that's what play looks like. It occurs spontaneously. You can study play. Bsed on water intake. You ahve to make the animal hungry for play. Namely they are isolated.. but then you have the problem that isolation or play deprivation, well play deprivation, if you take a little one and put it with an old friendly male, it doesn't want to play, but it has a big hunk of social companionship. The little one is still hungry for play. We don't know what's building up in the brain, but we know how play effects the rest of the brain.

We have the first psycho-assay as opposed to a behavioral assay  where we actually assay the positive feelings of the animal by tickling for 2 minutes. They go into the box, for 2 minutes, then we tickle. If the animal had nothing in there it might just show a couple of chirps. But just one tickle and the animal is enthusiastic for more. We are evaluating the animal's location and positive social feeling space and uh, and a psycho-assay should work the same in the hands of different individuals. So here we have, or at least these are male rats and female rats. And response to our assay behave the same. On themselves, older females remain more playful than older males. I am not implying upon our species.

Here are two separate experimenters, me a male tickler with 25 years of experience tickling animals. And my female lab manager who took care of the paperwork, she was not there to tickle rats, but I trained her, and she's doing it as well as I am, it's a learned skill. It's hard to learn it without someone showing you how to do it.

Falk Center for Molecular Therapeutics, Northwestern

I joined them for 6 years. They had the technology to ask if we could develop positive affect facilitators for depression. It took us a while to clarify the question. Then Washington State invited me, I finished my 3rd PhD in retirement. They let me keep my lab during that period. Joe Moskal. Jeff Burgdorf. Jeff, I am going to Washington, how about you get a postdoc and fill in my spot. And he filled the slot with youthful energy and he got more work done than I would have. So it was a good move. But we had already started the genetics of play and positive social feelings.

What do you do when you're looking for new antidepressants? Here's an old study. We want to know if play was a primary process. So at 3 days of age in rats we surgically remove the neocortex. The little ones are perfectly fine because they aren't using it yet. If you take it away when you're not needing it, they grow up fine like those children I showed you earlier. All the basic feelings. They show rage, fear, they copulate just fine. They have sex. Male as well as female. The mothers take care of the kids. Maternal behavior .. is int act without the neocortex. I am not saying this happens in our species, but rats without a neocortex do just fine in the laboratory but I expect they would be losers in the real world.

They also play normally. I got weirded out by this. I said, I'm going to do a laboratory practicum where I have 16 students in a laboratory class, and they are learning about brain and behavior. The first week of classes, I'm going to prepare 2 animals for eah of your students. One will be a.. normal. One will be... you will be learn about brain and behavior for 16 weeks. The last practicum is that each student individually will get 2 animals individually, you will observe the naimal for 1/2 hour, and do whatever you wish taht is not nasty, and you will tell me which one is the decorticut... I thought it would be a toss of the coin. They chose 12 decorticuts to be normal. What's the deal here? These animals in the world.. they have no worries. They are seeking, they come into a box, the experimenter is there. The normal animals go into a corner, but these guys are friendly and more interesting. They are more active, they are more childish. And people said, well that must be the normal animal.

But look what happens in the cortex. An animal that hasn't played doesn't have these fine dots. Every dots is a nerve cell. Was a nerve cell active? It turns out that the whole cortex becomes active durign play. You can take the cortex off early in life, and youcan play normally, so play natural play helps program social cortex I think. If we don't let our kids play, or our animals to play, not just Mickey Mouse video games and such, real social playing and generating their own games, we will have our own problems on our hands. The biggest problem is ADHD and it's because the top of the brain has not been adequately programmed by experience. If we do not allow play in animals, they show ADHD symptoms and they don't know how to regulat etheir behavior. EThey have impulse control problems. Every ADHD medication is a play reducer. All the psychostimulants reduce play. We have asked Washington for a play sanctuary where kids on the ADHD track are allowed to have free play in 30 minutes in the morning, 30 minutes in the evening,that's how much we need just like the other animals. We have been turned down 3 times. We're not ready for that one. That's another story.

The story that I want to tell you very briefly to summarize this article.. we looked at the gene expression of animals that had 1/2 hour of pure positive play, no negative stuff.. We listen into the chirps, happy sounds, no complaints. Of course there are lots of complaints eventually in play. "Oh you pushed me too hard, I'll tell mom on you know". You try to negotiate see if mom is on your side, a wise mom says "these things happen" and "get back there, get over it". Rats also begin to complain. So we have cortices where we haven't listened in yet.. okay, we're not going to waste time and microarrays to measure gene expression patterns, we are only going to measure animals that have positive play. So we went back to the drawing boards. So we did the front and back of the cortex at 1 hour after play, and 6 hours after play.

Frequency-modulated 50 khz ultrasonic vocalizations: a tool for uncovering the molecular substrates of positive affect

One third of the genes were shifted upwards or downwards after 1 hour. After 6 hours the system has settled down pretty much. So now we have 17 candidates, the overlap, the gene that was activated in both the front the executive thinking areas, and the back sensory perception areas, if the gene was in both areas, then it became a candidate. The very first gene was a wonderful growth factor, insulin-like growth factor 1. A growth factor, if you don't have that gene active when you're born, you die, you don't survive. We know that older people that have more of that growth factor circulating are the well adjusted happy elderly. They have higher circulating levels. So we asked, does this make rats more happy? Do they chirp more when we tickle them? Yes. If we block the system, they chirp less. So it was a target for antidepressant behavior, but it also facilitates cancer growth. You're not going to give a medicine that does tumor growth.

The next one, and we found that, but this may not mean much to you, we find that a subunit of a receptor that is within the glutumate excitatory amino acid family, if you're still listening and processing, your glutamate is very active in our brain. Every one of our thoughts has glutmate at the middle of it. If it is overstimulated you get epilepsy. If you want to produce anesthesia, ketamine which is a great anesthestic, blocks the system. It takes away consciousness. Every one of our thoughts has glutamate at the heart of it. It is also an amino acid, every emotion is controlled by. That's hard to find a medicine for. Remember, Michael Jackson killed himself, what did he kill himself with? Propophol, which is an anesthetic, he could sleep if he had the right dose, but he overdosed and went to sleep permanently. It was a great sleeping pill, but dangerous. He felt better the next day, that's why he took it. It's known that if you block the glutmate system, you bounce back out of depression very rapidly but just for short periods. So we're in the right ball game, so we started to develop or thinking about molecules for this and it turned out that we already have a molecule, but first of all, this is gene expression here in the venn diagrams. Here is the actual messenger RNA, mRNA, significant evaluation. See how the NR2B protein for this receptor for ... we're increasing a cognitive necessity of the brain using play, and we're taking play away from our kids? We finally developed a molecule called GLYX-13 that elevates social joy, here's normal tickle response, when we give GLYX-13 it dramatically elevates joy. If we block this system, it reduces social joy. This is a side on the glutamate receptor that receives glycine, another amino acid, and this is a potential target for antidepressants. We did toxicology on this for animals, you can't kill animals with this. LD50.. al ethal dose that will kill 50% of the animals. We could not find that LD50, it was so safe. So at that point you have to do human tox, and see if it has a side effect. Turns out there was no identifiable side effect. At that point you start looking for venture capital, and that was in the middle of the last recession caused by scandalous economic policies. VC was hard to find. Joe kept searching for 4 years, and finally VC bought it. They bought it for $60M which is what it requires to do the first Food and Drug Administration test. It was divided into 4 groups. That allowed the first clinical trial and it passed. They sold it to .. Spa Pharmaceutical Firm, for $30M, it had antidepressant effects better than anything out there. It was safe, the antidepressant effect was 1 week, it happened during the first day, then it requires 7 days, right now it is a sustained treatment. Once it, if it passes that, then it can go to phase 3 which is double blind placebo effect. So that's about $125M so you can imagine what that takes.

The bottom line is this: if we take the emotional feelings of animals seriously, we are going to be able to understand our own emotions and we will also progress in medicinal development. So far every psychological drug out there was discovered by chance and not by human knowledge. If GLYX-13 comes to market, it will be the first medicine for psychology that was ever developed by human knowledge, developed by human ingenuity regarding emotional feelings based on a psychoassay on tickling rats. You will find a BBC clip from 1998 if you look for panksepp tickled rats. Our official publications were turned down for years because studying laughter in rats would have to be nonsense. I appreciate you listening.