NEUR 402 Exam 2

Molecular control of neural fate and function

1. choice in neural lineage
2. inhibitory vs. excitatory
3. plasticity

What establishes neural origin, fate, and function?

cell intrinsic mechanisms (TFs and epigenetics)

What happens when generating neural lineage?

1. ectoderm first derives neural lineage from the 3 germ layers of a blastula before gastrulation (ectoderm, endoderm, gastroderm)
2. neuro epithilial or neuron stem cell
3. neuroprogenitor cell
4. then differentiates between excitatory and inhibitory


1. progenitor differentiation in neurons with neurotransmitter identity

plasticity of neuronal function

* neurotransmitter switching
* neural activity dependent transcription
* molecular ability to response → happens from transcriptomics and chromatin

chordin and noggin

* = BMP antagonists for neural induction
* BMP is found everywhere in ectoderm → specify for epithelial cells
* becuz of this, chordin and noggin diffuse into the overlying **ectoderm** to induce **neural fate ( =** **brain and spinal cord**) that are BMP antagonists and inhibit BMP signalling
* inhibition of BMP comes from TFs

core TFs that define pluripotency

SOX2, NANOG, OCT4

SOX2

* parent TF for everything
* Sox2 is a binding partner of Oct 4
* regulates self renewal
* if inhibited → goes to differentiation genes
* if unregulated → goes to self-renewal genes → maintenance, proliferation
* Sox2 is a binding partner of Pax 6
* regulates NE cells
* binds to promoter of Pax6
* inhibits mesoderm genes and endoderm genes
* upregulated Tfs to do neurogenesis → upregulated neurogenesis genes and notch signalling unregulated them as well
* binds to pluripotency genes in ESCs facilitated by interactions **with Oct4**
* Sox2 and Oct4 sit on promoter and turns **pluripotency** genes on


* binds to pluripotency genes in ESCs facilitated by **loss of Oct4**
* Oct4 depletes becuz BMP is turned off and nanog as well so Sox2 is then free to bind to other genes and turn them on with chromatin remodeling factor
* this turns on **neural progenitor** genes!!!

Why does neural lineage genes in SCs capable of being rapidly regulated

doesn’t require induction so it is faster

how is the chromatin remodeled?

chromatin remodeling proteins are recruited by TFs to remodel chromatin

* can be activated (HATs, enhancer regions, H3K4, HMT, etc)
* can be repressed (HDACs, repressor mechs on enhancer regions, H3K9 HMT, etc.)

poised

* = bivalent state of on and off
* **developmental genes** in ESCs and neural precursors
* marks key developmental genes the ability to respond to TFs (which then calls remodeling complexes)

histone mods

done at promoter and enhancer regions to establish their regulatory status

mechs for generating neural lineage

* polycomb → bound to every developmental gene and it is a supressor that is highly expressed in SCs
* abundantly expressed TF ready to initiate lineage (ectoderm BMP inibiting)
* permissive chromatin underlying neural genes ready to be expressed and made accessible in early developmental state → make the default state stay or change depending

how are excitatory and inhibitory neurons in neocortex established?

* TFs!!! → made the decision of what neurotransmitter (excitatory or inhibitory) first and then establish function later
* done in early stages of development
* generation of excitatory and inhibitory neurons have different origins
* excitatory migrate radially with radial glia cell and inhibitory migrate tangentially

generation of neurons in neocortex

* in teleencephalon
* proneurogenesis → symmetric proliferative divisions where one NEC (neuro ectodermal cells) splits to two NEC → makes copies
* when switching to neurogenesis → NEC transitions to RGC (radio glial cells → true progenital (NPC) cells to astro and oligo)
* neurogenesis → **asymmetric neurogenic division** that produces one copy of itself and then a neuron (1RGC + 1neuron)
* this asymmetric division establishes decrease Notch in presumptive pro-neural cells

notch pathway

* on → downregulates proneural genes
* delta = ligand for notch
* cleaved inside cyto part NICD when ligand-bound → turns on Hes genes

proneural genes

upregulated cell cycle arrest (no more growth) and neuronal differentiation

morphogens

ligands that recuruit Tfs

* generates region-specific use of TFs (dorsal - ventral / anterior - posterior) → the Tfs then go and establish the initial identity of neurotransmitters/neurons

notochord

rod-like, future vertebrae, underneath neural tube, secretes Shh

RGC differentiation in development

this is stage-dependent and timed! → RGCs change over time

* mid-gestation → astrocyte
* late gestation → oligodendrocyte

what is the plasticity of neural function?

* subtle changes in the genome that occur to modify a differentiated neuron’s path
* differentiated neurons actively gain and maintain bivalent status of neural genome
* can undergo target dependent switch of neurotransmitters of sympathetic neurons (sweat glands only want inhibitory neurons so if it gets an excitatory it tells it to go back and change to become an inhibitory and it does)
* this is done during development with sympathetic neurons with their subtype diversification of noradrenergic and cholinergic sympathetic neurons based on a principle of cross-repressive functions of TFs
* in summary:
* neurotransmitter is identified early on
* plasticity in neurotransmitter identity
* TFs common to multiple neurotransmitters part of plasticity
* differentiated neurons have ACTIVE transcriptome giving them the ability to respond

IEG

Immediate Early Gene = a set of genes that are rapidly expressed during stimulation (ex: Npas4)

Fos

* Ca in neuron
* Fos/Jun → SWI/SNF and IEGs → AP1 recruits CRCs and all other genes by binding to its own enhancers
* not active but poised cuz of pol → bound and ready to go but need productive elongation signal → that is it needs to phosphorylized

IEG txn

* activated by Ca
* neural activity dependent on it
* IEG responds right after stimulus and LRG (Late response Genes) respond after a long period of time

what happened when there was an increase in life expectancy?

increase in neurodegenerative diseases in populations (vaccine developments helped increase life expectancy)

AD overview

* cannot tell who has AD even with short convos
* 10 Early Symptoms
* memory loss that disrupts daily life
* challenges in planning or solving problems
* difficulty completing familiar tasks (basic ones already able to do)
* confusion with time and place (pt-dependent on which is worse)
* trouble understanding visual images and spatial relationships
* new problems with words in speaking and writing
* misplacing things and losing the ability to retrace steps
* decreased or poor judgement
* withdrawal from work or social activities (include environment)
* changes in mood and personality (can be very quick changes)
* type of dementia → causes problems with memory, thinking and behavior → symptoms develop slowly and get worse over time → eventually severe enough to interfere with daily tasks
* most common cause of dementia (= general term for memory loss and other cognitive abilities serious enough to interfere with daily life)
* not normal part of aging → can have early-onset AD as well before 65 yo
* progressive disease → symptoms worsen gradually over number of years
* 6th leading cause of death in US → average person lives 4-8 yrs after diagnosis (can be up to 20 yrs depending on other factors)
* has no current cure → Tx for symptoms

Why the AD research was slow before 1970?

it was rare, there were limitations in medical research techniques, and considered normal aging

Major pathological hallmarks of AD

* neurofibrillary tangles = Tau tangles
* amyloid plaques = Abeta (amyloid-beta)
* neuronal loss

Dx of AD pts

* clinical symptoms
* brain pathology
* PET and PIB-PET imaging
* biomarkers (?)
* two and three helpful if brain biopsy is unavailable

PET and PIB-PET examination of AD pt

increase of blue and green (low brain activity) rather than red (high brain activity) → shows decreased brain metabolic activity due to AD

* PIB-PET recognizes A-beta and plaques

amyloid-beta aggregation

* earliest pathological event in AD
* soluble A-beta accumulation in **CSF** begins 15-20 yrs before clinical symptoms occur
* biomarkers → connecter CSF

etiology of AD

genetic factors:

* mendelian genes: **APP, presenin1/2**
* risk genes:APOEe4, TREM2
* risk loci: SORL1, Picalm, CD33, ABCA7, PYK2

environmental factors:

* aging
* females:males (3:2)
* chronic inflammation
* brain injury (stroke)
* diabetes

History of genetic studies of AD

1987: mendelian gene studies by linkage analysis for Early onset AD → APP Preseniliin1/2 → associated with increased A-beta production

1993: risk gene studies by linkage analysis for LO AD → ApoE4

2005: GWAS

2011: Exome seq

AD hypothesises:

A-beta hypothesis:

* supported by human genetic studies → mendelian genes, risk genes, risk loci
* cleaved by microglial cells
* glial cells are impaired and prevents them to uptake A-beta → therefore leads to increase in A-beta production
* APP mutations → all beta or gamma site, 2pt mutation, beta cleave mutation site
* in line with dynamic progressive changes of AD
* supported by mouse genetic studies and cellular studies
* cascade of A-beta hypothesis → beta is toxic (missense mutations in APP or presenilin 1/2 or failure of A-beta clearance mechs)

Tau hypothesis:

* in line with dynamic progressive changes of AD
* supported by mouse genetic studies (increase in tau tangles gives u neuron loss) and frontal lobe dementia gives you earlier onset AD
* tau “spreading”
* prion-like transmission and spreading of tau pathology
* tau “infection” → pt brain extract is abnormal → phosphotase can get from abnormal tau to healthy brain

Microglia/Neuro-Immune/inflammation hypothesis:

* blood has huge increase of blood CSF
* microglia play important role in pathogenesis of AD → neurotoxicity of microglial activiation
* resident inate immune cells of CNS → macrophage residue in brain
* adult brain: maintain CNS homeostasis, provide immune response to injury
* AD pathology: increased neurotoxic inflammatory reactivity, reduced microglial clearance of A-beta activity

Multi-hit hypothesis:

* genetic factors are the primary hit
* environmental factors are the secondary hit

Angiopatahy, **Vascular Dementia**, and AD

* frontal dementia → rare
* vascular dementia → relevent and clinically matters as stroke = less blood flow to brain = increase risk for AD

lymphatic sys and AD

BBP deficit with high BP; clearance of beta in the brain

hydrogenous group → eventually some diff in the system

could AD be a systematic disorder?

* start in peripheral and then goes in to the brain
* genetic factors (primary hit) and environmental factors (secondary hit) lead to **BONE → critical site for blood cell and immune cell production and function**
* pts with AD have: lower BMI and BMD and higher rates of hip fracture
* TfAPPswe: aging gives u decrease bone formation, increase bone marrow fat, increase bone resorption
* AD-relevant phenotypes: decrease LTP, increase in A-beta plaques, increase in membry deficit

PD

a movement disorder with symptoms of resting tremor, slow movement, slow speech, rigidity (noticable things when you see a person) and the second most common neurodegenerative disease

* distinguishable “Archimedian” spiral drawn by a PD pt with tremor

how PD is identified

* English surgeon James Parkinson whose face is unknown had described 6 pt symptoms: resting tremors (shaking palsy), abnormal posture, gait difficulties, reduced muscle strength
* Jean-Martin Charcot named the disease Parkinson

PD brain pathology, DX and therapy

Major PD brain pathology:

* DA (dopamine) neuron loss → DA hypothesis
* alpha-synuclein+ Lewy body

DA hypothesis tested in animal models:

* local injection of 6-OHDA into midbrain → causes acute degeneration of DA neurons
* MPTP -monoaminooxidase> MPP → DA neurodegeneration
* DAT (dopamine transporter)-SPECT(single positron emitting computed tomography): used to image presynaptic DA uptake → loss of it shown in it
* L-DOPA Tx supports this as DA precursor of NE from tyrosine → clinically relevant drugs alter life cycle of DA becuz of this (MOA inhibitors and entacapone)

Dopaminergic pathways

* **nigrostriatal pathway**
* **substantia nigra to striatum**
* **motor control**
* **death of neurons in this pathway results to PD**
* tuberoinfundibular pathway
* hypothalamus to pituitary
* hor regulation
* maternal behavior (nurturing)
* preggo
* sensory processes
* mesolimbic mesocortical pathways
* ventral tegmental area to nucleus accumbens, amygdala and hippo and prefrontal cortex
* memory
* motivation and emotional response
* reward and desire
* can cause hallucinations and schizophrenia if not functioning properly
* cocaine and amphetamine targets dopaminergic synapses

Tardive dyskinesia (TD)

a movement disorder that causes involuntary, repetitive body movements and is commonly seen in pts who are on long-term Tx with antipsychotic medications

* can show similar symptoms of PD but primarily caused by antipsychotic medications that chronically blocks D2 receptors and cause them to upregulate and having a slow onset (tardive) and presence of involuntary movements (dyskinesia) that can be potentially permanent

PD Tx: DBS (deep brain stimulation)

* done especially if symptoms cannot be adequately controlled with meds
* surgical option of this offer symptomatic benefit → ease symptoms but not proven to change underlying course of disease
* delivers electrical pulses to brain cells to decrease symptoms

PD Etiology

genetic:

* **autosomal dominant PD: VPS35**, SNCA, LRRK2
* **autosomall recessive PD**: PINK1, Parkin, DJ-1…
* **other genes associated with atypical PD**: ATP13A2, FBX07


* environment:
* age: over 60 (1%), over 80 (5%)
* gender (males>females)
* brain-inflammation (pesticides)
* brain/head injury
* smoking?
* linkage analysis from 1997 gave alpha-synuclein as a hypothesis
* prevelance of PD in OH in highest cohort → rates highest in midwest and northeast regions

could PD be systematic disorder?

in 1872, Dr. Charcot described in detail the arthritic changes, dys-autonomia and pain that can accompany with PD

* PD relationship with bone: pts with PD have lower BMI and BMD, higher rates of arthritic changes, and Paget Disease of Bone (PDB → earlier onset PDB-like deficit in PD-like mutant mice with decrease of OB genesis and bone formation and increase OC genesis and bone resorption giving it PDB-like deficit
* PD-relevant phenotypes: increase in alpha-synuclein and decrease in DA neurons

basic architecture of cerebellum

* has a cortex (cerebellar cortex) and subcortical nuclei (deep cerebellar nuclei = collections of nerve cell bodies)
* three layers (cerebral cortex has 6)
* repeated circuit motif performing basic computations
* basic cerebellar circuit performs the same computations across the cerebellum → main diff between cerebellar regions being the source of the inputs and the destination of the outputs

What does Cerebellum do?

* traditionally thought of as primarily devoted to motor control → ablation in cerebellum gives deficits in motor behavior, coordination, lack of repetitive things and smoothness → not actual motor movements (primary motor cortex)
* cerebellum DOESN’T function in initiation or selection of motor behavior or programs → instead makes programs ‘better’, imparting smoothness, coordination, speed, and makes them automatic (ex: in humans without need for conscious oversight)
* suggests cerebellum also contributes to execution of non-motor functions, including cognitive functions
* **cerebellum as a device for associative (procedural) learning** → thought to play a role of learning smoothness in movement → do simple tasks without thinking about every move (“think about every movement before I do it like grabbing a cup of coffee”)

affects of cerebellury injury and disease

* ataxia = disordered movement
* decomposition of movements → try to do something but broken up into steps
* dysmetria = inability to control distance, speed, and range of motion necessary to perform smoothly coordinated movements
* dysrhythmia = poor sequencing of movements
* intention tremor
* loss of ‘automaticity’

clinical tests of cerebellar function

* finger to nose test
* rapid alternating movements
* tandem walking

ex: adaptive control of stimulus/response relations (what does cerebellum do)

* there is a diverse sensory input to the cerebellum imparted on a reflex system → makes the reflex system work better (changes it) through training
* becuz cerebellum is a device used for learning → its contributions to motor behavior develop as a result of experience through process of procedural learning
* changes in synaptic strength (NMDA coincidence detectors) and intrinsic ability →which is how neuroplasticity comes to be)

examples of cerebellar learning

1. adaption of the vestibulo-ocular reflex (VOR)


1. basically have glasses that act like magnifying glasses and skew your vision and see how vision is adjusted with the position of the eyes → measures this with gain = eye velocity/head velocity (should be 1)
2. if VOR is not there → it is very disorienting
3. retinal slip = effectiveness of VOR
2. learned motor performance task


1. prism glasses trying to hit target → you can adapt after a while
2. those with PICA (posterior inferior cerebellar artery) occlusion due to a stroke can’t every hit the target and adapt
3. eyeblink conditioning


1. uses pavlov conditioning → best studied and understood example
2. ablation to cerebellum = animal not having a conditioned response to a stimulus that usually has been trained to make u close your eyes

structural subdivisions of the cerebellum

vermis, hemisphere, paravernis, anterior lobe, posterior lobe, flocculonodular lobe

the functional subdivisions of the cerebellum

spinocerebellum, cerebrocerebellum, vestibulocerebellum

spinocerebellum

vernis, controls axial neurons and spine

cerebrocerebellum

hemisphere, helps smoothness of eyemoves and involves the cerebral cortex

vestibulocerebellum

floculonodular, controls the vestibular

subcortical structures

deep cerebellar nuclei → inside the cerebellar cortex and broken down to the dentate, emboliform, globose, fastigial

how the cerebellum communicates with other brain regions

* **inputs and outputs!**
* diverse sensory inputs → cerebellar cortex → deep cerebellar nuclei → reflex center output
* cerebellum consists of parasagittal modules that have distinct inputs and outputs but **have similar internal circuitry →** maybe similar computations/operations carried out on the imputs from different sources provide outputs to various destination structures

cerebellar cortex

* consists of 3 layers organized into repeated sagittal zones → 2 inputs, 1 output
* input 1: mossy fiber input to cortex
* input 2: climbing fiber input to cortex
* three layers: molecular layer (its interneurons are all inhibitory), granule layer, and white matter
* purkinje cell in its own layer (purkinje cell layer) sends the output to basket cells or stellate cells in molecular layer → has spontaneous activity → bifurcates and goest to other places
* granule cell in granular layer has no spontaneous activity → produces parallel fibers in molecular layer → weak and need lots to send input
* basic circuit in picture

synaptic responses of purkinje neurons to 2 extrinsic inputs

* extrinsic inputs = parallel fibers inputs (1) and climbing fiber inputs (2)
* parallel fiber stimulation → potentiate together rapidly and continuously
* climbing fiber stimulation → spread out and short bursts
* purkinje → inhibitory, GABA → an increase in this means a decrease in other neuron responses cuz its inhibitory
* granule cells → excitatory glutamate
* stimulating climbing fiber gives you a complex spike → neurotransmitter is aspartate

classical conditioning

* **delay conditioning** = US (unconditioned stimulus) co-terminates with CS (condition stimulus) or immediately follows it → no memory system needed
* **trace conditioning** = CS and US are separated in time by an interval → memory system needed

cerebellum and eyeblink conditioning

* cerebellum is required for EBC → if removed, the previously acquired conditioned EBC responses are lost as is the ability to learn new conditioned responses
* if cerebellar cortex is lesioned → ability to learn new conditioned responses is lost, but previously learned responses are preserved with modified timing
* if deep cerebellar nucleus that participates in conditioned response reversibly inactivated → previously learned conditioned responses are inhibited but recover as does the ability to learn new associations

EBC experiment

* EBC mechanism → if CS and US done multiple times together then CS will do circuitry by itself → overtime the coincidence of CS and US increases synaptic strength so purkinje fibers (inhibitory and spontaneous) are inhibited to project to the reflex system
* extinction of purkinje is found after repetitive of __CS only presentation__ → no more silencing (purkinje doing the inhibition as it is being inhibited)
* purkinje does pausing IF there is **CS and US paired**
* after conditioning → there is an increase of firing rate because the purkinje is silenced
* where is the site of plasticity?
* three places → deep cerebellar nucleus, synapse between climbing fiber and inhibitory interneurons, end axons of purkinje cell
* __*ex: increase in purkinje strength → increases firing to purkinje =* ***pauses*** *as there is a decrease going to deep cerebellar nucleus*__
* __*same thing but there is a decrease in strength in purkinje = decrease firing to purkinje =* ***no pausing*** *cuz increase in DCN*__
* __*climbing fiber and inhibitory interneuron → increase strength = decrease purkinje firing = increase DCN = no pausing*__
* __*decrease strength = increase purkinje firing = decrease DN = pausing*__
* __*DCN → increase strength = no pausing*__
* __*decrease strength = pausing*__

why study hippo

* essential for certain forms of memory → anxiety, social memory
* most studied brain area, many of the general principles of modern neuroscience established → nice model sys - allows you to study electrical, molecular, dendritic, synaptic
* hippo CA1 pyramidal neuron is perhaps most studied neuron → synaptic transmission, LTP, dendritic integration

contributions of hippo research to general principles

* general principles of physiological properties of hippo CA1 pyramidal neurons can be applied to most pyramidal neurons → from axon = axon initial segment AP, but dendritic AP
* first use of microelectrodes for extracellular neuronal studies
* development of tetrodes for unit recording in behaving animals in vivo
* use of extracellular field synaptic potentials and pop spikes as tools for data analysis → sun lab
* intracellular recording for central nervous sys
* brain slice preparations for neuroscience research
* computational modelling

hippo

* dorsal: spatial recognition
* ventral: anxiety, social behavior

hippo anatomy

* hippo proper = CA1, CA2, CA3


* hippo formation = CA, dentate gyrus (DG), entorhinal cortex (EC), subiculus, pre and para subiculum
* hilus = reciprocally connected to DG

Hippo circuitry

* trisynaptic pathway:
* entorhinal cortex -layer II perforant path> DG -mossy fiber> CA3 (can connect back to itself: recurrent collateral) -Schaffer collateral> (synapse here most studied) CA1
* direct pathway:
* entorhinal cortex - layer III perforant path> CA1 __***OR***__
* entorhinal cortex -layer II perforant path> CA3 (can connect back to itself: recurrent collateral) -Schaffer collateral> (synapse here most studied) CA1
* skips DG

hippo beyond spatial memory

* essential for episodic memory (ex: last night dinner? who did you eat with?)
* involved in emotion and anxiety (ventral hippo has massive reciprocal connections with amygdala
* regulation of hypothalamic functions (ex: feeding behavior) → central hippo
* **participate in social behavior and memory**
* but also spatial memory
* **dorsal CA2, ventral CA1 and CA3 also important for social memory**
* dorsal CA2 to CA1 proximal → social memory (ventral CA3 involved in → social memory)

Heterogeneity of hippo principal neurons

* 3 anatomical axes
* proximal - distal (transverse)
* deep - superficial (radial)
* dorsal - ventral (long)

hippo rhythms

* theta: 4-12 Hz
* learning memory, help organize between different regions
* gamma: 25-100 Hz (inhibitory GABA)
* plays role similar to theta
* sharp-wave ripple: 110-250 Hz ripples superimposed on 0.01-3 Hz sharp waves
* memory consolidation

Hippo abnormality and disease partial list

* chronic stress (DG atropy)
* AD
* temporal lope epilepsy (HM)
* depression
* PTSD (pre-frontal cortex, amygdala, hippo)
* anxiety disorders (ventral hippo → ventral CA1 anxiety cell)
* schizophrenia
* cognitive ageing

engram

* Karl Lashley
* physical location in brain where memory was stored
* if taken out → problem relocating a memory (ex: 15th birthday)
* if one engram was affected the others would not be affected
* experiment: rats were trained to run a maze (run same mazy a day so became very efficient) → this became a proxy for a hippo memory engram → used this to make a jump from the cellular sys to what changes when you learn/experience something (STM you can be sure, you can’t with LTM) → then took out neocortex of rat after maze learned
* results → location didn’t matter, took random parts of neocortex and percentage of it → linear with number of errors
* if it was engram → if the piece which stores the maze memory was taken then there would be an increase in errors and if any other piece was taken there would be no errors or few → NOT THE CASE
* results pointed to there being NO ENGRAM

HM

* anterograde amnesia = defect in memories that are newly formed → **hippo was responsible for this**
* bilateral temporal lobe resection → removed both hippo and associated structures
* even if he met someone millions of times (Brenda Milner) → he would meet them as a new person every time because he had no memory stored of meeting her
* Brenda Milner → discovered HM could form new long-term nondeclarative memories (ex: priming and mirror drawing)
* mirror drawing was done as there was no baseline for HM and easier as it was linear

declarative memory

memory for an event, place, or person

theories of where memories were located

* penfield = specific places (electrical stimulation)
* lashley = distributed (graded memory impairment - rats)
* HM = global memory impairment for localized lesion
* **hippo → involved in making LTM (declarative) but it is not where it resides!!!**

Major themes of memory function

1. there are different types of memory
2. each type of memory is processed and stored in different brain regions
3. formation of LTMs occurs in stages
4. storage of LTMs is distributed

three forms of memory (Brenda Milner - HM)

1. Long-term declarative (**explicit**): neocortex in medial temporal lobe


1. places, facts, events, people
2. Long-term nondeclarative (**implicit**): striatum, cerebellum, neocortex


1. unconscious (ex: practice freethrows everyday → get better after a yr and you don’t know how u got there; another ex: piano)
2. another ex: priming!!! → talk a lot about apples then ask 20 min later for a word that starts with A
3. Short-term (**working memory**): prefrontal neocortex


1. ex: phone number → rush to memorize it and write it down before it is gone

consolidation pathway theory - memory

prefrontal cortex (working memory) → hippo → temporal lobe neocortex (explicit memory)

* consolidation of LTMs occurs in stages → takes time for it to become a LTM

memory formation

population of neurons become quiescent and start oscilating together (40-80 Hz) → every neuron holding information on this same memory have to be in oscillation and synchronized with consciousness involved too (whether you want to memorize it or not) → if there is info out of sync it will not be remembered → communication theory of coherence

* type of memory is spatially localized and come from very different brain areas → one brain area has a certain memory of the 15th birthday (color) and another brain area has the ppl who came to the birthday party

specificity of inferotemporal cortex neurons - memory

* located at the bottom of the temporal lobe
* face cells = this cell neuron drives from faces seeing faces
* experiment: monkey watching images and see the firing rate of face cells

working memory in prefrontal neocortex

* experiment with monkey given a delayed response test → put ball under cup → distraction delay → get monkey to point which cup has a ball
* another experiment done with delay response task: stare at focal point and not move head, light on = cue, after some time it turns off but central light still on, another delay, then central turns off and eye saccade given as response
* three types of responses from prefrontal cortex:
* two trivial: cue (sensory), and response (motor)
* one interesting: delay period (memory?)
* delay period neurons are direction-selective → can predict incorrect response before the animal makes the response

key points for peripheral chemical sense **olfaction**

* large family of odorant receptors
* individual odorant receptors can detect **multiple** odorants
* each olfactory sensory neuron expresses a single type of receptor
* olfactory receptor neurons → olfactory bulb → olfactory tract → primary olfactory cortex (medial temporal lobe)
* **divergence, convergence, and divergence again, with modulations**
* pheromone = specialized odor, animals have specialized systems just for pheromone processing
* olfactory sys between insects and mammals has many similarities
* detection of bad food necessary for health

key points for peripheral chemical sense **taste**

* **sweet, sour, bitter, salty, and umami**
* basic taste qualities are detected by G protein-coupled type 1 and type 2 taste receptors (sweet, umami, bitter) and by other receptors and ion channels (salty, sour) and possibly by transporters
* taste signals travel from taste buds on tongue
* taste receptor cells on tongue → cranial nerves VII and IX → nucleus solitaries (brainstem) → thalamus → bilateral taste cortices (fronto-parietal lobes
* like pheromone in olfaction, the taste system (at least drosophila) also has **specialized processing center that evaluated food acceptance or rejection**

olfaction pathway

* odorant → **olfactory epithelium** → __olfactory bulb__ → *olfactory cortex*
* **olfactory sensory neurons** → criboform plate → __glomeruli with tufted cells and mitral cells__ → *pyramidal cells*
* molecular signaling used to generate neural activity in olfactory epithelium is involved in synapse formation → molecules involved in axon separation → involved in determining the projection positions → and zone to zone circuit wiring of olfactory sys

differences in olfactory systems between insects and mammals

* they don’t transmembrane G protein receptor with signaling cascade that amplifies the signal for the cell to depolarize
* pheromone processing (drosophila) → highest sensitivity and specificity in the world
* antennal lobe as first-order processing center instead of olfactory bulb
* simpler system in insects than mammals as it is more complex
* mushroom body and lateral protocerebrum (lateral horn) as second-order processing centers (olfactory cortex, entorhinal cortex, piriform cortex, amygdala and so on in mammals)
* ORCO (olfactory receptor co-receptor) in insects that is inhibited by DEET (most effective insect repellent)
* insect legs can smell
* bombykol → extreme sensitivity of male moths to female pheromones arises from pushing olfactory systems nearly to their physical and chemical limits → sex pheromone in moths → process from initial detection to AP is the FIRST in the world
* loss of VNO in aquatic same as a reduction in olfactory receptor and a devolution of the main olfactory system
* aquatic snakes also have valves in their nostrils that allow them to breathe while submerged whereas other aquatic snakes don’t have that and must come to the surface to breathe air
* sniff in mammals → active sampling of the environment as an odor detection by becoming intelligent by reducing interaction with environment
* insects use odor plumes → passive sampling by enhancing interaction with the environment and not needing to make brain bigger

similarities in olfactory systems between insects and mammals

* olfactory receptor neuron
* amphibians are ready and adapted to either aquatic or terrestrial environment
* there is a general and innate pathway for both
* the general pathway is more or less the same with different structures but the set up is similar

divergence, convergence, with divergence again, with modulations

* OE → OB has this happen fast whereas OB → amygdala is slow
* its literally the fact that our cells can detect many odorants so they diverge in the OE, converge in the OB and then diverge depending on if it is the innate or general pathway

Innate Pathway - Olfaction

* OE → OB → amygdala
* this pathway is done if there is an instinctive smell or something for a specific aversion stress response or an attraction relaxation response
* general pathway is for everything else no associated with either aversion or attraction!
* modulation of olfaction based on neural activity and aversion small receptors (these are farther away in the nose as there is less stimulation needed for it to be activated)

pheromone

* = specialized odor with specialized systems just reserved for its processing (vomeronasal organ)
* pathway: sensory neurons (or receptor neurons) in antenna and maxillary pulp → antennal lobe as first-order processing center (OB in mammals) → mushroom body and lateral protocerebrum (lateral horn) as second-order processing centers (olfactory cortex, entorhinal cortex, piriform cortex, amygdala and so on in mammals)

xenopus oocytes (frog)

* used with HEK 293 cells for olfactory receptor research
* useful because they allow us to perform two-electrode voltage-clamp electrophysiology

sweet

T1R2/T1R3 and GPCR and type II

umami

T1R1/T1R3 and GPCR and type II

bitter

T2Rs and GPCR and type II

salty

ligand gated chanel for Na (ENaC) and type III

sour

ligand gated channel for Na and H (PKD2L1 plus TRCs) and type III

taste buds

small organ in the tongue where taste signals travel and they are localized in the edge of the tongue

type I taste cell

supporting cell with glial property

type II taste cell

GPCR receptors

type III taste cell

ligand binding receptors

taste cell types and their interactions

1. self to self interactions
2. type II to type III
3. type III to sensory afferent fibre