 Hello and welcome to Physiology Open. Humans have different states of brain arousal ranging from awake and alert to sleep which itself consists of different stages that is NREM sleep with four stages and REM sleep but how do we change brain states between different states of arousal that is how do we actually switch from wakefulness to sleep and then from NREM to REM sleep and then again from sleep to wakefulness so basically there are switches of arousal states happening one here from awake to NREM then one here from NREM to REM and then from REM to awake state after a substantial duration of sleep is over now if there is any trouble in making the switch we get sleep disorders example a switch from awake to sleep state is excessively delayed it's a sleep initiation disorder then with the induction of sleep you should first enter NREM sleep and not into REM sleep directly if that happens that is also a disorder it happens in narcolepsy then secondly once you enter a state that state should be maintained for a specific duration so once you are awake that state should be maintained and you should not feel sleepy for a considerable amount of time in a day that will be abnormal isn't it? Similarly once you sleep that should also be maintained it should not be that you wake up frequently in between sleep so how these complicated phenomena of induction of a brain state and then its maintenance actually happen let's dive straight into the circuitry and talk about its various components so one component is ascending reticular activating system or RAS present in brain stem then two major areas in hypothalamus that is a tubular mammillary nucleus in posterior hypothalamus and a vlpo or ventrolateral pre-optic nucleus in anterior hypothalamus and finally basal forebrain now these areas have different types of neurons in the terms of which neurotransmitter they release and which arousal state they are active this ascending reticular activating system and posterior hypothalamus have neurons which are wake-on neurons that is they are active during a wake state posterior hypothalamus has system-energic neurons and in RAS there are two areas one is a locus cellulose with norepinephrinegic neurons and the other is dorsal rapid nucleus which has serotonergic neurons so all these neurons are wake-on neurons and we can call these as wake-promoting areas then this anterior hypothalamus that is vlpo and basal forebrain have GABA agit neurons that is neurons which release GABA and are active during anarium phase of sleep so these are anarium on neurons so we can call this area as sleep-promoting area now with this logic there should be some neurons which are active during REM sleep also yes there are neurons in this reticular activating system in lateral dorsal tegmental nucleus that is LDT and pedunculopontine tegmental nucleus that is PPT nucleus which reveals acetylcholine and are REM-on neurons also this basal forebrain has some acetylcholine secreting neurons which are active in wake as well as in REM sleep so these are wake-on REM-on neurons now remember all these neurons project to cerebral cortex via hypothalamus and produce characteristic EEG waves of each brain state okay before you get confused with so many nuclei and neurons let me simplify this little bit for you see that the hypothalamic neurons are involved in wakefulness and anarium sleep so there is interaction among these hypothalamic neurons to switch between wakefulness and anarium sleep right while these brain stem RAS neurons are involved in wakefulness and REM sleep so there is interaction between this reticular system nuclei for switching from REM sleep to wakefulness okay and there is interaction between these hypothalamic and brain stem nuclei to switch between anarium and REM sleep and to fine-tune other switches okay so how does interaction between these different types of neurons causes switch between different states see state switching is kind of a seesaw till the time one side is more powerful it keeps the state to itself however the other side also keeps trying then after some time some factors weigh in which increase the weight of other side and decrease that of the first side and that time state switching occurs so let's understand this in terms of neuronal activity and connections in a simplify the scheme all wake on neurons should inhibit sleep neurons and sleep neurons should inhibit all wake on neurons with balance tilting to each side with time so let's start from the time when we are awake so based on the discussion till now can you tell which neurons are active when we are awake and which are inactive yes all these three wake on neurons that is a norepinephrine energetic serotonergic and histamineergic neurons are active and all sleep neurons that is naryamon and remon neurons are inactive and by similar logic we can tell that to fall asleep that is to enter naryam sleep naryamon neuron should become active and the wake on neuron should be inhibited so what happens during the wake state all these wake on neurons keep these sleep neurons inhibited actually histamineergic hypothalamic neurons inhibit naryamon neurons and RAS norepinephrineergic and serotonergic neurons inhibit rm on neurons see i told you before that hypothalamic neurons are involved in wakefulness and naryam sleep and RAS neurons are involved in wakefulness and rem sleep so hypothalamic wake on neurons inhibit naryamon neurons and RAS wake on neurons inhibit remon neurons but one more interesting thing here that this histaminergic neurons actually excite these LDTPPT acetylcholine releasing remon neurons and the basal brain acetylcholine releasing wake on remon neurons this is because along with histamine acetylcholine also maintains alert brain state so if we see in terms of neurotransmitters during wake state particle histamine serotonin and noradrenaline levels will be high acetylcholine will also be seen while GABA levels will be very low now while we are awake we should remain awake for a considerable time isn't it so a wake state should be self-sustaining that is it should promote itself for this there exists a positive feedback low so see this connection here histamine wake on neurons excite basal form brain wake on remon neurons which in turn excite one more very important set of wake on neurons that is a hypochritin wake on neurons present in lateral hypothalamus these hypochritin wake on neurons in turn excite histamine wake on neuron so it appears there is a never ending loop here which sustains wake state but this loop needs to be stopped after sometime so that we can sleep isn't it so there is another control over these hypochritin neurons the other wake on neurons which we stated that is RAS neurons actually inhibit these hypochritin wake on neurons which in turn activate these norepinephrine serotonergic neuron so in this loop hypochritin neurons are promoting their own inhibition while in the other loop which we talked first hypochritin neurons are promoting their own activation see this is a positive feedback here right also these norepinephrine and serotonergic neurons tend to inhibit themselves too so their inhibition on hypochritin wake on neurons will not be that much effective during wake state because they are inhibiting themselves so till the time this effect is powerful wake state will be maintained now for the initiation of sleep basically two things can be done either the self-sustaining loop should switch off this will make these wake on neurons less powerful and thus inhibition of vlpo activity by wake on neurons will decrease or with time these vlpo anarium on neuron should become more powerful and inhibit these wake on neurons thus decreasing the activity in this self-sustaining loop basically both types of activity are happening in body for the first one that is the switching of this loop these hypochritin neurons which we spoke of act as switching center basically for the switch if we can make these neurons less active their excitation input to all wake on neurons will decrease hence these wake on neurons will no longer be able to inhibit sleep neurons powerfully so anarium on neurons will resume activity isn't it actually these hypochritin neurons are sensitive to environmental cues for example glucose and leptin levels in blood which indicate welfare state inhibits these neurons on the other hand ghrelin a hormone important for initiation of me stimulates these neurons so in welfare state these neurons will become less active while in hunger they are more active so are you getting now why they feel sleep after a good meal while hunger keeps us awake then they also receive information from suprachiasmatic nucleus that's why our wake sleep cycle is affected by light then information from limbic system that is the amygdala also goes there so you know why emotional states interfere with induction of sleep or sometimes prevent waking up that is a person does not want to get out of bed it depends on how limbic system is influencing these hypochritin neurons now the second one even these anarium on neurons can be made more powerful actually like this separate control is working for wake on neurons a separate control is also working for these anarium on neurons these neurons are kept inhibited by other neurons also now adenosine or metabolite accumulates in weightfulness due to increased brain activity especially in basal forebrain this inhibits these inhibiting neurons causing disinhibition of plpo anarium on neurons so once they become disinhibited they become powerful and they in turn inhibit the wake on neurons thus initiating sleep and inhibit these hypochritin neurons also making themselves more and more powerful and hence also maintaining anarium sleep so this effect of adenosine on induction of sleep is known as metabolite theory of sleep so when adenosine is more there is induction of sleep and as sleep progresses this metabolite concentration goes down again its effect decreases and anarium on neurons again become inactive do you know that why having a strong cup of coffee keeps us awake well the caffeine blocks the adenosine receptors and prevents adenosine from acting and hence prevents induction of sleep anyways now can you tell what will be the cortical concentration of neurotransmitters in anarium sleep well cortical GABA levels will be high because we are seeing anarium on neurons release GABA but other neurotransmitters that is the norepinephrine serotonin histamine and acetylcholine will be low okay let's go to next level how a switch is made from anarium to REM sleep remember that these anarium neurons inhibit all wake on neurons so even these serotonergic and norepinephrine energy neurons are inhibited so as sleep progresses anarium neurons exert more inhibition of these wake on neurons and rars so that they no more inhibit REM neurons so after sometime threshold is reached causing switch to REM sleep so neurotransmitter wise during REM sleep there will be quite high acetylcholine but lesser norepinephrine serotonin and histamine see acetylcholine is present in cortex during wakefulness also but much less than that in REM sleep since norepinephrine and serotonin neurons are inhibiting these acetylcholine producing remone neurons during wakefulness okay let's now see the final one that how from REM sleep switch happens to wake state well here between wake on neurons and anarium on neurons we saw mutual inhibition but here between wake on neurons and remone neurons we have cycling behavior that is these neurons inhibit and remone neuron but remone neurons actually excite these wake on neurons so when remone neurons become active during REM sleep they excite these wake on neurons of rars more and more and hence causing wakefulness okay i know the connections are quite complex but you think of this simplify the scheme first then project it to complex circuit this will help you remember the circuit of induction and maintenance of various brain estates thanks for watching the video if you like did do like and share the video and don't forget to subscribe to the channel Physiology Open thank you