the brain

see also:

• brain evolution and development
• cerebrospinal fluid (CSF)
• stroke (CVA)
• neurology
• consciousness
• memory
• speech
• modelling the brain:
  • Dec 2023: Uni of Cambridge, UK, announces by using their new concept 3D “spatially embedded recurrent neural networks” (seRNNs) they have created a self-organizing, artificially intelligent system that uses the same tricks as the human brain to solve specific tasks. The seRNNs converged on structural and functional features that are also commonly found in primate cerebral cortices. ¹⁾

• in humans, the brain is the most expensive organ in the body requiring 20% of our energy
• the brain also has 25% of the body's cholesterol which is essential for the structure and function of neurons

• in neurons, the transport process of mitochondria is determining, since these organelles must be present along all axons and dendrites - neuron extensions - to provide energy to the neurotransmission and the neuronal functions, processes that require a lot of energy. This great consumption depends on a specific and precise distribution of mitochondria within neurons - the Alex3/Gαq mitochondrial complex interacts with the mitochondria machinery to distribute and transport these cell organelles along the neurons' axons and dendrite. This process depends on the interaction of the Gq protein with the Alex3 mitochondrial protein. The Alex3/Gαq is essential not only for the transport and mitochondrial function, but also for neuronal physiology, movement control and neuronal viability. The interaction of the Alex3/Gαq mitochondrial complex is regulated through the G protein-coupled receptors (GPCR). The activation of GPCRs not only alters the mitochondrial distribution but also its function, and as a notable effect, the neuronal growth and viability. Different functions played by the Alex3 protein could be associated with many pathologies such as neurodegenerative diseases. Loss of Alex3/Gαq may result in neuronal death. Mutations in the gene that codes for Gαq in humans lead to motor disorders, cognitive deficits, intellectual disability and epilepsy.²⁾

• a 2023 single-cell chromatin atlas study ³⁾ of 1.1million brain cells in 42 distinct brain regions from three donor human brains and revealed 107 different subtypes of brain cells:
  • 924,016 were non-neurons - 65% were OGC; 14% ASCT, 12% MGC, 7.5% OPC
    • glial cells play an important role in homeostatic brain functions, such as regulating blood flow and in removing synaptic debris
    • they also appear to be directly involved in learning, memory, and cognition
    • Oligodendrocytes (OGC) - 3 types
    • Oligodendrocytes precursor cells (OPC)
    • Committed oligodendrocytes cells (COP)
    • astrocytes
      • physiology:
        • have a primary cell body (soma) with numerous branching processes that envelope nearby neuronal synapses resulting in potentially more than one million “tripartite” synapses per cell forming astrocyte networks which spatially tile the brain, forming nonoverlapping “islands”
        • astrocyte processes detect neurotransmitters in the synaptic cleft, leading to an upsurge in intracellular free calcium ions within the astrocyte process, this leads to a biochemical cascade in the astrocyte, potentially culminating in the release of gliotransmitters (the main gliotransmitters are glutamate, ATP, and D-serine in addition to homocysteic acid, taurine, atrial natriuretic factor, tumor necrosis factor-alpha, GABA, and some peptides and cytokines) back into the synaptic cleft, influencing neural activity—a closed feedback loop
        • astrocyte processes can intercommunicate through calcium transport, and individual astrocytes connect via gap junctions
        • respond to neural activity on timescales spanning many orders of magnitude, from several hundred milliseconds to minutes
      • general roles:
        • serve a crucial role in directly sensing neural activity and, in turn, regulating synaptic strength and plasticity
        • are important targets of neuromodulatory signals such as norepinephrine and acetylcholine emerging from potentially distant brain structures such as the brainstem
        • are necessary for forming and retrieving long-term memories (i.e., by participating in engrams) ⁴⁾
      • Telencephalon astrocytes - 3 types
      • Non-telencephalon astrocytes - 3 types
    • Microglia (MGC) - 2 types
      • specialized brain-resident macrophages that arise from primitive macrophages colonizing the embryonic brain and are the main immune cells that act as the brains dedicated defense system
      • play a crucial role in regulating the number of cells that become neurons in the brain in early human brain development via a key pathway of lipid-mediated crosstalk between microglia and neuronal progenitor cells that leads to improved neurogenesis ⁵⁾
    • Bergmann glia
    • Endothelial cells
    • Vascular smooth muscle cells
  • 133,612 were Glutamatergic neurons - 37% were CBGRC, 26% ITL2/3, 6.3% ITL5, 5.8% ITL4, 5.1% ITV1C
    • Granule neurons from cerebellum (CBGRC)
    • Intratelencephalic projecting neurons, cortical layer 2/3 (ITL2/3) - 6 types
    • Intratelencephalic projecting neurons, cortical layer 5 (ITL5)- 4 types
    • Intratelencephalic projecting neurons, cortical layer 4 (ITL4)- 2 types
    • Intratelencephalic projecting neurons from primary visual cortex (ITV1C) - 3 types
    • Glutamatergic neurons from amygdala
    • Cholinergic neurons
    • L6 corticothalamic (CT) projection neurons - 2 types
    • Extratelencephalic projecting neurons
    • Near-projecting neurons - 3 types
    • Glutamatergic neurons from entorhinal cortex - 2 types
    • Glutamatergic neurons from piriform cortex
    • Glutamatergic neurons from temporal pole (TP)
    • Glutamatergic neurons from subicular cortex
  • 76,732 were GABAergic neurons - 19% were VIP, 19% SST, 17% MSN, 13% PVALB, 6.7% SNCG
    • VIP+ GABAergic neurons - 7 types
    • SST+ GABAergic neurons - 5 types + SST+ GABAergic neurons with CHODL+
    • Medium spiny neurons (MSN) - 3 types
    • PVALB+ GABAergic neurons - 4 types plus PVALB+ chandelier cells
    • SNCG+ GABAergic neurons - 5 types
    • GABAergic neurons from thalamus - 2 types
    • GABAergic neurons from Inferior colliculus and nearby nuclei - IC
    • D1- and/or D2- medium spiny neurons - from nucleus Accumbens, from body of the Caudate, from putamen
    • LAMP5+ GABAergic neurons - 2 types
    • GABAergic neurons from septal nuclei
    • GABAergic neurons from mediodorsal nucleus
    • GABAergic neurons from Inferior colliculus and nearby nuclei - 2 types
    • GABAergic neurons from midbrain mixed with cell from cerebral nuclei
    • GABAergic neurons from cerebral nuclei - 2 types
    • FOXP2+ GABAergic neurons from cerebral nuclei - 4 types
    • Purkinje cells - 2 types
    • Inhibitory neurons from cerebellum
    • GABAergic neurons from basal nuclei
    • Inhibitory neurons from basal forebrain and extended amygdala
  • uncovered the state of chromatin accessibility at 544,735 putative transcriptional regulatory elements in these cell types
  • linked many putative transcriptional regulatory elements to potential target genes
  • developed model to predict disease relevant cell types for 19 neuropsychiatric traits and disorders
  • developed machine learning models to predict the regulatory function of disease risk variants
  • identified that ~1/3rd of human brain candidate cis-regulatory elements (cCREs) showed conservation and accessibility in the mouse brain
  • made this atlas freely available to the public through an interactive web portal CATLAS

• neocortex:
  • 75% of the human brain is the neocortex which:
    • learns a predictive model of the world - understands the physical characteristics of objects, where they are located, how they behave
    • can consider both physical and abstract objects
    • learn languages, etc
  • originally it was thought to be an vertical hierarchical architecture but it has been shown to be far more horizontally interconnected and complicated between the 150,000 basic neocortical neuronal physiologic sensorimotor units of 6 layered 1mm² neuronal columns which are all thought to have same intrinsic function but actual function depends upon what they are connected to.
  • there are dozens of different types of neurons which are roughly distributed into layers
  • all regions have a motor output
• allocortex
  • 10% of the cortex in humans and has 3-4 layers
  • enterorhinal cortex
    • located in the medial temporal lobe and is the main interface between the hippocampus and neocortex and is a major player in memory processing
    • has grid cells which create reference frames of environments such as a room to allow mapping of the environment and moving the body within the environment and allow navigation
    • it is thought similar grid cells are also in the neocortical columns to allow mapping of objects
• thalamus
  • acts as a relay station, or hub, relaying information between different subcortical areas and the cerebral cortex
  • every sensory system (with the exception of the olfactory system) includes a thalamic nucleus that receives sensory signals and sends them to the associated primary cortical area
  • plays an important role in regulating states of sleep and wakefulness
    • damage to the thalamus can lead to permanent coma
    • thalamo-cortico-thalamic circuits are believed to be involved with consciousness
    • the mediodorsal thalamus (MD) may play a broader role in cognition
• basal ganglia
  • striatal, pallidal, nigral, and subthalamic parts
  • the dorsal striatum is divided by a large tract called the internal capsule into two masses named the caudate nucleus and the putamen
  • the putamen and globus pallidus make up the lentiform nucleus
  • associated with motor planning and control, cognition, emotions, learning, and domain-general functions important for executive functioning as well as support for domain-specific languages.
• limbic system
  • a set of brain structures located on both sides of the thalamus
  • hippocampus - consolidation of new memories
  • amygdala - emotional processes
  • nucleus accumbens - involved in reward, pleasure, and addiction
  • hypothalamus - regulates many autonomic processes
    • asprosin, a hormone (discovered in 2016), is known to stimulate food intake and maintain body weight by activating key 'hunger' neurons in a part of the brain called the hypothalamus
  • mammillary bodies
  • anterior nuclei of thalamus - receive input from the mammillary bodies and involved in memory processing
  • highly conserved male mating circuit in mice and presumably in all mammals:
    • pheromonal chemosensory input to Substance P neurons in the bed nucleus of the stria terminalis (BNST) in the amygdala (these distinguish between sexes and guide mating toward females and aggression toward males) excite POA^Tacr1 neurons in the preoptic hypothalamus with Substance P receptors, these in turn release dopamine for the reward system and self-stimulation of these cells via activation of neurons in the ventral tegmental area (VTA) which then stimulate neurons in the nucleus accumbaris (NAc) ⁶⁾
    • this controls sexual recognition of potential mates, libido, and mating behavior including refractory period between mating, and pleasure
    • an embedded molecular timer delays mating onset following mate recognition
    • Determination of mate:
      • “Estrogen receptor alpha (Esr1 or ERα)-expressing BNSTpr (BNSTpr^Esr1) neurons consist of molecularly diverse cells as defined by single-nucleus RNA sequencing (snRNA-seq). Male aromatase-expressing BNSTpr^Esr1 (BNSTpr^Aro) neurons are differentially activated by females and required to distinguish between sexes. Of all BNSTpr^Esr1 neurons, only the transcriptomically defined BNSTpr^Tac1 cell type (a subset of BNSTpr^Aro neurons) is essential to distinguish between sexes. Furthermore, inhibition of male BNSTpr^Tac1 but not other BNSTpr^Esr1 neurons essentially abrogates mating and aggression.”..“the activity of BNSTpr^Tac1 neurons of sexually naive males distinguishes between sexes and reflects mating”..“activation of BNSTpr^Tac1 neurons induces males to treat males as females” ⁷⁾
    • Mating latency reduction:
      • “activation of POA^Tac1 cells reduced mating latency and elicited time-locked mating”.. “and suppressed aggression and elicited time-locked mating attempts toward males” ..thus .. “drives mating at the expense of aggression”⁸⁾
    • Mating:
      • “POA^Tac1 neurons are active during mating, and their activity is necessary and sufficient for mating (sic. mounting behaviour and intromission) but not aggression (sic. nor sniffing behaviours)”.. “Substance P, encoded by Tac1, is expressed in the BNSTpr, and among tachykinin neuropeptides, it is the cognate ligand for the receptor Tacr1, which is important for male mating”⁹⁾
• midbrain
  • aka mesencephalon, the rostral-most portion of the brainstem connecting the diencephalon and cerebrum with the pons
  • includes cerebral peduncles, tegmentum, and tectum (“roof”)
  • functionally associated with vision, hearing, motor control, sleep and wakefulness, arousal (alertness), and temperature regulation
  • higher order sensory nuclei such as inf and sup colliculi for sound and vision respectively
    • superior colliculus:
      • helps animals orient themselves toward important locations in space, like directing their eyes and head toward a bright flash of light
      • also plays a role in complex cognitive tasks like visual categorization and decision making ¹⁰⁾
  • reticular formation nuclei such as locus caerulus
• hindbrain
  • aka rhombencephalon;
  • includes:
    • pons and medulla of the brainstem
      • cranial nerve nuclei, etc
    • cerebellum
      • makes up just 10% of the brain's total volume but has more than half of the brain's 86 billion nerve cells
      • it has key roles in emotional processing as well as gait and balance
      • PTSD patients have cerebellums about 2% smaller and the worse the PTSD, the smaller the cerebellum ¹¹⁾
      • a hormone, asprosin, crosses from the periphery into the brain to activate Purkinje neurons in the cerebellum. This leads to an enhanced drive to seek and drink water and thus modulates control of thirst ¹²⁾
• blood-brain barrier (BBB)
  • this prevents the transfer of larger molecules into the brain unless there are transport systems for these or the barrier is disrupted
  • choline is transported into the brain by a protein called FLVCR2 ¹³⁾

• a network that basically operates all the time and maintains our spontaneous stream of consciousness
• it's associated with the “default” patterns of thought that happen in the absence of specific mental tasks and includes day dreaming, meditation and other internally focused types of thinking and is likely to the be initiator of creative thoughts before being evaluated in other systems ¹⁴⁾
• the DMN is spread out across many dispersed brain regions, making it more difficult to track its activity in real time
• it is connected to the anterior hippocampus and is thought to create our sense of space, time and self
• The activity of the network is changed in several disorders, such as ruminative depression, in which the DMN is more active than normal, possibly related to increased dwelling on negative internally directed thoughts
• psilocybin causes significant disruptions in brain functional connectivity (FC), particularly in the default mode network, linked to subjective experiences and lasting for weeks, which may underlie its therapeutic effects¹⁵⁾. Via serotonin 2A (5-HT2A) receptor activation, it can induce significant acute and persistent changes in self, time, and space perception.
• in patients with epilepsy, it seems that when the two hippocampi start communicating with each other then this raises the risk of a seizure within the next hours or day.¹⁶⁾

• discovered in 2012, the glymphatic system is a “pseudo-lymphatic” perivascular network distributed throughout the brain, responsible for replenishing as well as cleansing the brain.
• glymphatic clearance is the macroscopic process of convective fluid transport in which harmful interstitial metabolic waste products are removed from the brain intima
• sleep is a primary driver of glymphatic clearance - there appears to be a 90% reduction in glymphatic clearance during wakefulness, and twice the amount of protein clearance from the brain intima during sleep - and it appears that the majority of glymphatic clearance activity occurs during N3 sleep which occurs in non-REM deep sleep and glymphatic transport is most efficient in the right lateral sleeping position, with more CSF clearance occurring compared to supine and prone. ¹⁷⁾
• it appears to reduce in efficiency as we age
• low doses of alcohol (0.5 g/kg) appears to increase glymphatic clearance but higher levels reduce it
• glymphatic clearance can be manipulated by sleep deprivation, cisterna magna puncture, acetazolamide or genetic deletion of AQP4 channels

• intracellular haemoglobin
  • within astrocyte nucleoli it acts as a “pseudoperoxidase” breaking down H₂O₂ into water however its levels are also reduced by high levels of H₂O₂
  • in 2025, it was found a substance KDS12025 is able to cross the BBB and bind to astrocyte haemoglobin's heme center and boosts its ability to decompose H₂O₂ by nearly 100-fold, without disrupting its normal oxygen-carrying function ¹⁸⁾