Contemporary Advances in Neuroscience
Week 1 — From past to future: how did neuroscience begin and where is it taking us?
Topic 1: Looking back to move forward — a brief history of neuroscience (Part 1 of 3)
Definition of neuroscience: the study of the brain and the nervous system in health and disease.
Levels and approaches: molecular, cellular, synaptic, network, computational, behavioural; often multiple levels used together.
Interdisciplinarity: history shows disciplines feeding into applied neuroscience; brain and behaviour studied from many origins.
History linked to technology and instruments; conceptualisations tethered to cutting-edge tools.
Early sign of brain importance observed even in prehistoric times (e.g., evidence of brain as important).
Trepanation: skulls showing surgical holes, often with bone growth around the site indicating survival; some individuals underwent multiple trepanations.
Theories: removal of demons or treatment for disease/mental illness; modern parallel: release of intracranial swelling.
Medical benefit recognized in some cases (conceptually analogous to relieving swelling).
Tools: flint-knapped blades (obsidian) used; other materials found nearby.
Contemporary claim: underground trepanation enthusiasts exist; some use it for higher consciousness (not recommended).
Egyptians (about 5,000+ years ago): brain discarded during mummification; hooks used to reach the cranial cavity and remove brain tissue; heart preserved for afterlife relevance.
Edwin Smith Surgical Papyrus: oldest medical text; observed brain paralysis and lack of sensation from nerve damage; argued about brain connections.
Classical Greece and Hippocrates: humoral theory (blood, phlegm, yellow bile, black bile); illness linked to humoral balance; emphasis on observation and balance rather than divine causes.
Shakespearean cosmology later incorporated humors as personality qualities.
Galen: ventricles important for transmitting messages to/from brain; influenced thinking for ~1,500 years.
17th century: Descartes — dualism vs monism; brain/body mechanical but mind non-physical; animals as automatons influenced experimental approach; problem: mind cannot be studied scientifically if non-physical.
17th–18th centuries: Thomas Willis (The Anatomy of the Brain, 1664) — reflexes, epilepsy, apoplexy; term ‘neurology’; Circle of Willis.
Anton van Leeuwenhoek (1674): first microscope; foundation for anatomy of nervous system.
Electricity and neuroscience: Luigi Galvani’s frog-leg experiments; electricity as key driver of nervous transmission; Mary Shelley’s Frankenstein linked to electricity as life-force (“electricity reanimates tissue”).
Bell–Magendie law: first clear evidence of directional information flow in nerves; sensory input travels one way, motor output another.
Darwin and Wallace: evolution; brain and emotion; commonalities across species.
Darwin’s Emotion book: emotional expression parallels with animals; brain controls behaviour across species.
Part 2: Transition to modern neuroscience—figures and milestones
17th–19th centuries: phrenology (Gall, Spurzheim) proposed localised function based on skull bumps; later discredited as a legitimate science, but important for localisation concept.
Mark Twain tested phrenology; exposed lack of validity; nonetheless, phrenology popularised localisation ideas.
Early localisation work: Flourens (lesioning/ablation); Broca (language production; Broca’s area via patient TAN); Fritsch & Hitzig (in vivo motor cortex mapping; contralateral control).
Golgi vs Cajal debate: Golgi stain showed neurons; Cajal argued for neuron doctrine (discrete cells communicating via synapses).
Nobel Prize 1906 awarded to both Golgi and Cajal for contrasting but complementary contributions.
John Hughlings Jackson: hierarchy of processing (spinal cord → brainstem → cortex); predictive framework for lesion effects.
Otto Loewi (1921): chemical transmission evinced; vagus nerve stimulation slows heart rate; acetylcholine identified; evidence for electrochemical transmission.
Charles Sherrington: synapse concept; timing of transmission longer than pure electrical conduction would predict; coined ‘synapse’.
By the mid- to late-20th century: a rapid acceleration in neuroscience.
Innovations in imaging, genetics, and neurophysiology accelerate understanding of brain function.
1970: Society for Neuroscience founded (≈500 members then; ≈40,000 today).
1984: Human Genome Project planned; 1990s launch; public understanding and funding increase.
1992: first use of fMRI to map human brain activity.
2013: Obama’s BRAIN Initiative (Connectome emphasis) launched to map neural connections.
Core guiding framework for modern science:
Four foundational actions in neuroscience: identify it, map it, observe it, manipulate it.
Emphasis on observation and experimentation, building on prior work.
Resources and further reading:
Society for Neuroscience (history and resources)
Milestones in Neuroscience (Eric Chudler) for timeline-style overview
Topic 2: Neural Stem Cells — a contemporary dual tool for modelling disease and therapeutics
NSCs defined: undifferentiated cells with self-renewal and multipotency; generate neurons, astrocytes, oligodendrocytes.
Symmetric division → self-renewal; symmetric or asymmetric divisions produce progenitors with restricted fates.
Potency framework:
Totipotent: can form all cell types and whole organism (e.g., fertilized egg up to day 4).
Example: fertilized egg; can form placenta and embryo.
Pluripotent: can form all tissue types but not an entire organism (e.g., inner cell mass of blastocyst; iPS cells).
Multipotent: restricted to limited lineages within a tissue (e.g., NSCs → neurons, astrocytes, oligodendrocytes).
Exercise: name a tissue origin for each potency class.
Origins during development:
Neural plate stage; neural plate cells; neural tube; neuroepithelial cells; radial glial cells (cortex); multipotent progenitors.
In adulthood, NSCs largely reside in the dentate gyrus (DG) of the hippocampus and the subventricular zone (SVZ).
Adult neurogenesis contributes to learning, memory, mood regulation, and possibly stress response.
NSC identity markers and identification challenges:
Sox2 (early neural plate, ubiquitous; becomes restricted to neural stem cell pools)
Nestin (intermediate filament protein; neural stem/progenitor marker)
Musashi (RNA-binding protein; persists in embryonic and adult NSCs)
Markers can be expressed in restricted progenitors; no single exclusive antigen; often a combination of positive/negative markers is used.
Techniques to identify dividing NSCs: BrdU labelling; retroviral GFP labeling (cell division introduces label into genome).
In vivo markers can change with position (spatial) and developmental age (temporal).
Sources and derivation of NSCs for research/therapy:
Developmental sources: blastocyst (inner cell mass), gastrula, embryonic neural plate; early neural tube stages.
Adult sources: hippocampal DG, SVZ; other non-neural multipotent cells as potential NSC sources (bone marrow-derived MSCs, hematopoietic stem cells, adipose-derived stem cells).
Induced pluripotent stem cells (iPSCs) as a route to neural stem cells via reprogramming differentiated cells.
In vitro control of proliferation and differentiation requires tightly regulated growth factors, signaling pathways, and transcription factors; long-term stability and genetic integrity must be demonstrated before transplantation.
Dual-use potential of NSCs:
Research tool: fundamental discovery (gene discovery, microRNA studies, disease modeling).
Disease modelling: using patient-derived or engineered NSCs to model neurodevelopmental and neurodegenerative conditions; drug screening and mechanism studies.
Regenerative medicine: transplantation for spinal cord injury and neurodegenerative diseases; challenges include cell-host interactions, immunology, and tissue integration.
Sources of NSCs for transplantation and ethical considerations:
Foetal brain tissue (pros: biological maturity, potentially robust plasticity; cons: ethical/regulatory concerns; immune rejection; risk of tumorigenesis if immortalised).
Embryonic stem cell lines (blastocyst-derived) as an alternative to foetal tissue; broader tissue plasticity; ethical concerns about embryo use.
Somatic cells reprogrammed into iPSCs for autologous NSCs; avoids immune rejection but is technically challenging and time-consuming.
Adult brain NSCs from the patient (autologous) or donor tissue; potential limitations in yield and expansion.
Practical/technical considerations for future work:
In vitro expansion, purification, banking; cell sorting; maintaining genetic stability; controlling proliferation/differentiation.
Cell-host interactions, immunology, and transplantation biology considerations for successful grafting.
Carrier development and infrastructure for clinical translation.
Example applications and future directions:
In research: human foetal hippocampal NSCs used to identify genes/microRNAs involved in proliferation and neural differentiation; cortisol-stress models to study neurogenesis and antidepressant rescue.
iPS cells to model disease and to study drug repositioning; potential for personalised medicine.
Topic 3: Neural Stem Cells — gene editing (CRISPR) and therapies
Transition to Topic 3: CRISPR as a transformative genome-editing tool for disease modelling and therapy, including ALS, Huntington's disease, etc.
Patient-derived iPS cells vs isogenic controls:
Isogenic control lines: identical genetic background except for the disease-causing mutation; allows attribution of observed effects to the mutation.
CRISPR basics (summary of mechanism):
Cas9 nuclease guided by a small guide RNA (gRNA) targets a genomic sequence next to a PAM sequence (for SpCas9, PAM = NGG).
Double-strand breaks (DSBs) repaired via two main pathways:
Non-homologous end-joining (NHEJ): quick; error-prone; can introduce insertions/deletions leading to loss-of-function (“knockout”).
Nonsense-mediated decay can degrade transcripts with premature stop codons, silencing gene expression.
Homology-directed repair (HDR): uses a DNA repair template (often ssDNA ~100 bases) to introduce precise edits (point mutations, small insertions).
CRISPR can therefore knockout genes or introduce precise base changes to model disease or correct mutations.
Key cautions and challenges:
Off-target edits: undesired changes at similar genomic sites; mitigated by careful gRNA design and validation.
AAV packaging limit (~4.5 kb): limits the size of CRISPR components that can be delivered in a single vector; often two vectors used.
Practical examples and approaches:
Knocking out mutant disease alleles to reduce toxic protein expression in models (e.g., SOD1 in ALS mouse models; systemic AAV9-SOD1 targeting across brain).
HDR-based precise edits using AAV delivery with two vectors to fit payloads; achieving editing in ~10% of targeted neurons in mouse cortex (Neuron 2017 study).
Microsatellite repeat expansions (e.g., C9orf72) present a challenge for gene knockout; alternative strategies include RNA-targeting CRISPR to degrade toxic RNA foci (RNA-level CRISPR approaches).
CRISPR-derived approaches for neurological disease include base editing, prime editing, and RNA targeting to avoid DNA breaks.
Therapeutic potential and caveats:
In vivo gene editing as potential therapy for neurodegenerative and neurodevelopmental disorders.
Concerns about off-target effects, delivery methods, immune responses, and long-term safety.
CRISPR in a broader context:
The technology is rapidly evolving; current and forthcoming sections will cover further therapeutic strategies and ethical considerations.
Week 1 Wrap-up
Neuroscience defined; levels of analysis; interdisciplinary and historical perspectives.
Localisation of function evolved from phrenology to modern neuroanatomy; lesion studies and neurophysiology.
The shift from mystical/divine explanations to empirical, evidence-based neuroscience; the role of electricity in neural transmission.
Four recurring questions in neuroscience research: identify, map, observe, manipulate; importance of model systems and historical context.
Week 2 — Circuits and tracing: mapping the brain and optogenetics
Topic 1 — Traditional and contemporary lab techniques for mapping brain circuitry
Connectomics: goal to build wiring diagrams of brain networks; structure-function relationships; computational models of networks.
Golgi stain vs Ramon y Cajal: two foundational methods in neuroanatomy; Golgi stain reveals complete neuron morphology in a small subset of neurons; Cajal used it to classify neuron types and argue for the neuron doctrine.
Patch clamp (Biocytin labeling): live neurons; electrophysiology; morphological reconstruction via biocytin diffusion.
Anterograde vs retrograde tracing; lipophilic dyes (e.g., DiI) as classic tracers; cholera toxin B (CTB) as a retrograde tracer; retrobeads and Fluoro-Gold as retrograde tracers; limitations of directional specificity.
Astrocytic and neuronal markers; combining anatomical tracing with functional readouts.
Genetically encoded tracers: GFP and variants; Cre-LoxP system for cell-type specificity; AAV-based delivery for region-specific labelling; tissue clearing (clarity) to image whole brains.
Transsynaptic tracers: prion-like spread vs restricted spread; Pseudorabies virus (PRV) transsynaptic tracing; rabies virus-based monosynaptic tracing using EnvA-pseudotyped, G-deleted system; TVA receptor and Cre-dependent AAVs to target specific neurons; safety considerations and potential neurotoxicity.
GFP reconstitution across synaptic partners (GRASP): two split GFP halves reconstitute when neurons are connected; requires prior knowledge of partner neurons.
Validation and controls: genetic targeting; immunostaining to verify neurotransmitter identity; functional verification via electrophysiology.
Topic 1 — Part 2 (detailed connectomics experiments and genetic strategies, including Sox14 knock-in lines and dLGN interneurons)
Sox14 knock-in line used to label dLGN GABA interneurons; GFP reporter and cre driver used to selectively label interneurons.
AAV-mediated Cre-dependent expression of Channelrhodopsin (ChR2) to test functional connectivity via optogenetics and patch-clamp readouts.
In vivo/ ex vivo approaches: slice physiology; optogenetic stimulation to measure inhibitory postsynaptic currents via GABAergic interneurons.
In utero genetic labeling strategies reveal developmental origin of interneurons; midbrain origin and migration into dLGN at birth; evidence from in utero injections of Cre-dependent AAVs and subsequent birth-born labeling.
Retrograde and anterograde CTB labeling combined with GFP to map inputs and outputs in the dLGN; dissection of dorsal LGN (dLGN) which relays visual information to cortex; vLGN and IGL involvement in non-visual functions.
Topic 1 — Part 3 (Cre-Lox, viral tools, and transsynaptic tracing expansions)
Use of Cre- and AAV-based systems to drive expression of opsins (e.g., ChR2) in specific neural populations; combining with optical stimulation and electrophysiological readouts.
Monosynaptic rabies tracing: EnvA-pseudotyped rabies lacking the G gene restricts spread to one synapse; requires TVA and G complementation in starter cells.
Dual AAVs to supply necessary components (TVA and G) only in Cre-expressing cells; tracing inputs to defined cell types.
GFP reconstitution across synaptic partners and transsynaptic labeling limitations and strengths.
Transsynaptic viral-vector safety and biosafety considerations for mammalian work.
Topic 2 — Mapping the brain in practice
Visual pathway overview: retina → optic nerve → optic chiasm → dorsal lateral geniculate nucleus (dLGN) → V1; general thalamic role in synchronizing cortical activity and coordinating cross-modal processing.
Retina architecture: layers including ONL (photoreceptors), OPL, INL, IPL, GCL; cell types: rods, cones, horizontal, bipolar, amacrine, retinal ganglion cells (RGCs);
RGC diversity and parallel pathways encoding contours, color, motion, etc.; questions about how many RGC types exist and how many neuron types exist in dLGN.
Genetic labeling and imaging strategies to identify dLGN interneurons (Sox14 marker); using CTB tracer to label retinal innervation and compare with GFP-labeled dLGN neurons.
Use of two-photon imaging, GFP knock-ins, and immunohistochemistry to verify GABAergic identity of Sox14-labeled interneurons.
Combining optogenetics (ChR2) with Cre lines and AAVs to selectively activate Sox14-expressing interneurons and measure postsynaptic responses with whole-cell patch clamp.
Demonstrating that Sox14 interneurons in dLGN provide GABAergic inhibition to nearby neurons; Gabazine (GABA_A receptor antagonist) used to confirm GABAergic mechanism.
Embryonic targeting of dorsal midbrain to label interneurons before they migrate into the dLGN; in-utero injections to reveal migratory patterns.
Developmental origin of dLGN interneurons demonstrated by labeling neurons before birth; red fluorescent protein (Tomato) used to visualize targeted cells.
Mapping the retinal inputs to dLGN interneurons using transsynaptic rabies tracing; analysis of retinal ganglion cell (RGC) types that project to interneurons.
Dorsal midbrain origin of GABA interneurons and their later migration into dLGN after birth; strategies to identify specific RGC types innervating a given interneuron.
Topic 3 — What does optogenetics have to do with meditation? (Part 1 of 2)
PNAS paper: rhythmic optogenetic stimulation of ACC interneurons (parvalbumin-positive, PV) to model mindfulness training effects in mice;
Interneurons in ACC manipulated via two strategies:
PV-ChR2: activate PV interneurons → overall reduction of pyramidal neuron activity (inhibitory control).
PV-Arch (Arch): inhibit PV interneurons → disinhibition of pyramidal neurons → increased ACC network activity.
Behavioral readouts in light-dark box to measure anxiety-like behaviour; open-field tests for locomotion; novel object recognition for cognition.
Experimental design: 4 weeks of 20–30 min sessions; groups include PV-Arch, PV-ChR2, and PVPV-controls (no opsin); some groups compared to no-laser controls.
Neural readouts: electrophysiology showing frequency-dependent changes in pyramidal cell firing in response to light (1 Hz, 8 Hz, 40 Hz).
Topic 3 — Main conclusions and caveats
ACC interneuron manipulation can modify anxiety-like behaviour; activating PV interneurons reduces ACC output (more inhibition) and increases anxiety-, whereas inhibiting interneurons increases ACC activity and reduces anxiety-like measures in some contexts.
Findings are preliminary; small N; consider translational relevance and potential confounds (e.g., laser exposure effects in control groups).
Week 3 — Computational neuroscience and action selection
Topic 1 — Introduction to computational neuroscience
Core aim: mathematical modelling of neural cells, circuits, and networks to understand action selection and decision making.
Comparison of vertebrate basal ganglia with insect central complex (analogy across phyla): both mediate action selection and decision-making; both show modular circuit architectures.
Key components and analogies:
Basal ganglia (vertebrate): striatum (caudate + putamen) → GPi/SNr (output) → thalamus → cortex; direct pathway (D1) facilitates movement; indirect pathway (D2) inhibits movement; dopamine modulation balances these pathways.
Insect central complex: protocerebral bridge (PB), fan-shaped body (FB), ellipsoid body (EB), lateral accessory lobes (LAL); ring/columnar neurons encode sensory space; potential direct/indirect analogue pathways via EB/NO/LAL.
Neural representations and cognitive computation: salience, attention, and action selection emerge from population dynamics; networks combine multiple signals into coherent output.
Foundational concepts: neural signals can be treated as oscillations; phase space and attractors describe dynamic network states; Fourier transform allows decomposition into constituent frequencies; phase relationships across regions yield coordinated actions.
Key math and concepts (LaTeX):
Action potentials as quasi-periodic sine waves: x(t) ≈ Σk Ak sin(ωk t + φk). x(t) \approx \sum{k} Ak \,\sin(\omegak t + \phik)
Period and frequency relations: period T, angular frequency \omega = \frac{2\pi}{T}, frequency f = \frac{1}{T}.
Fourier transform concept: the time-domain signal x(t) can be represented by its frequency-domain components X(ω): X(\omega) = \int_{-\infty}^{\infty} x(t) e^{-i\omega t} dt.
Phase space and attractor: a dynamical system state x can be represented in a phase space with attractor A such that trajectories converge toward A; Lorenz attractor as a classic example of chaotic dynamics: dx/dt = σ(y − x), dy/dt = ρx − y − xz, dz/dt = xy − βz.
Conceptual takeaways:
Neuronal networks exhibit complex, nonlinear dynamics; single-neuron models (e.g., Hodgkin–Huxley) describe membrane potentials and ion-channel conductances; networks require higher-dimensional attractor analyses.
Nonlinear dynamics enable rapid, flexible behavioural responses near critical states; stability and robustness achieved via attractor structures and recurrent inhibition.
Topic 2 — Computational neuroscience: action selection in health and disease
Detailed comparison of basal ganglia and insect central complex in action selection:
Basal ganglia circuitry is organized into direct (D1) and indirect (D2) pathways; dopamine modulates the balance between facilitation and suppression of motor programs.
Insect central complex shows analogous architecture with columnar and ring neurons forming a modular representation of sensory space; theorized to support salience detection and selection.
Demonstrated that direct/indirect pathway-like dynamics can co-occur and cooperate rather than be strictly antagonistic.
Disease relevance: dyskinesia, Parkinson’s disease, dystonia, Tourette’s, OCD, schizophrenia all associated with impaired action selection due to disrupted basal ganglia circuits; analogous dysfunctions in insects may illuminate conserved principles.
Parkinson’s disease model in Drosophila: POL-Gα-IR manipulation; dopaminergic projections to EB/LAL; parallels to nigrostriatal loss in humans; demonstrates conserved DA modulation of action selection circuits.
Topic 3 — The future within reach: brain-machine interface and neuroprosthetics
Neuroprosthetics overview: devices that replace or augment input/output of nervous system; output interfaces translate brain intention to external actions; input interfaces translate environment into neural signals.
Clinical software/hardware spectrum: EEG-based non-invasive control; invasive implants delivering stimulation or recording neural activity; potential for motor, sensory, autonomic restoration.
Example: epidural electrical stimulation (EES) for spinal cord injury (SCI) to enable voluntary leg movements; implanted arrays and real-time control for locomotion.
Key study: Angeli et al. 2014 (SCI patients) showed partial restoration of voluntary movement with EES; treadmill and standing capabilities observed with stimulation during therapy; suggests spinal circuits below injury can be recruited.
Computational modelling and simulation work:
Finite-element modelling used to predict electrical field distribution during EES; neuron models integrated to assess circuit recruitment.
Closed-loop tuning of EES frequency improves motor trajectories (e.g., stair climbing in rat models).
Limitations and challenges:
Invasiveness; immune response; device longevity; need for robust control algorithms; reliance on robotic assistance in early stages.
Take-home messages: neuroprosthetics integrates neuroscience, engineering, and clinical practice to translate basic science into therapies; can restore aspects of motor function and independence in SCI, with ongoing improvements in control systems and surgical techniques.
Week 4 — Sleep, neuroplasticity, and neuroimaging advances
Topic 1 — Sleep: circadian rhythms and sleep stages
Sleep is a highly conserved, rhythmic behaviour with circadian regulation; total sleep-wake cycles vary across species.
Circadian regulator: Suprachiasmatic Nucleus (SCN) in the hypothalamus; entrained by environmental cues, notably light (via melanopsin-containing retinal ganglion cells).
Melanopsin-containing retinal ganglion cells respond to blue light and project to SCN; blue-light exposure can disrupt circadian rhythm; screens impact sleep patterns.
Sleep stages: Non-REM (NREM) and REM; NREM subdivided into stages 1–4 with slow-wave activity increasing; REM characterized by desynchronized EEG similar to wakefulness and muscle atonia.
Wakefulness shows desynchronized EEG with alpha rhythm; sleep deepens with slow-wave activity; REM sleep shows REM features including rapid eye movements and atonia.
Topic 2 — Sleep, memory, and neurogenesis
Neurobiology of sleep-wake control: cholinergic and monoaminergic ascending arousal systems:
Cholinergic (pedunculopontine and laterodorsal tegmental nuclei) project to thalamus and cortex; promote wakefulness and wake-related thalamocortical activity.
Monoaminergic (locus coeruleus, raphe nuclei, tuberomammillary nucleus, etc.) modulate cortex and arousal; activity high in wake, low in REM.
Preoptic area (VLPO) GABA/galanin neurons promote sleep by inhibiting ascending arousal systems.
Orexin (hypocretin) in the lateral hypothalamus stabilizes wakefulness and transitions; orexin deficiency linked to narcolepsy with sleep intrusions, cataplexy, fragmented sleep.
Sleep and memory: REM and non-REM stages contribute to memory consolidation; CREB and cAMP pathways modulated by sleep/wake cycles; adenosine builds with wakefulness and promotes sleep; caffeine antagonizes adenosine receptors.
Sleep deprivation disrupts hippocampal function; REM sleep linked to memory consolidation via CREB signaling; adenosine buildup correlates with sleep pressure.
Topic 3 — Super-resolution microscopy and neuroplasticity
Optical resolution limits: Abbe limit; light microscopy resolution ≈ λ/(2 NA) with typical visible light and high NA achieving ~200 nm; subcellular structures (proteins, receptors) require higher resolution.
Super-resolution techniques overcome diffraction limit; localisation-based methods (STORM, PALM) determine the center of blinking fluorophores across many frames to build high-resolution images.
Localisation microscopy principles: stochastic blinking of fluorophores; register multiple frames to compute sub-diffraction coordinates; many frames (thousands) required; precision depends on optics, labeling, and data processing.
Typical resolutions: ~10–15 nm achievable in ideal conditions; trade-offs exist between speed, field of view, and live imaging capability.
Practical applications: visualising synaptic proteins at sub-synaptic locations; understanding how neuromodulators and extracellular matrices influence synaptic organization.
Part 2 — Super-resolution microscopy and neuroplasticity
Application example: brevican and perineuronal nets surrounding parvalbumin-expressing interneurons; STORM used to map brevican localization relative to AMPA receptors (GluA1) at synapses.
Findings: brevican mutations alter synaptic AMPA receptor distribution (fewer synaptic GluA1, more extrasynaptic GluA1); reduced synaptic GluA1 density; activity-dependent changes in brevican expression.
Methods: electrophysiology (miniature EPSCs) showed lower frequency (not amplitude) of GluA1-mediated currents in brevican mutants; western blots revealed altered GluA1 distribution in synaptic vs non-synaptic membranes.
Behavioral correlation: brevican mutants show impaired short-term spatial working memory in T-maze tasks; long-term memory sometimes enhanced due to different memory consolidation mechanisms.
Conceptual take-home: activity modulates brevican levels in perineuronal nets, which in turn modulates AMPA receptor trafficking and synaptic strength; STORM enhances our view of subsynaptic organization and its plasticity.
Week 5 — Virtual reality (VR) in mental health and VR-based neuropsychological measures
Topic 1 — Virtual reality: introduction to VR and applications
VR defined: immersive, interactive 3D environments; sense of presence (feels like being there) drives authentic emotional and physiological responses.
VR systems: head-mounted displays (HMDs), CAVE environments, motion tracking; increasing immersion and interactivity (hand tracking, locomotion).
VR advantages in mental health: high ecological validity with experimental control; ability to simulate real-world contexts (shopping, public transport, social settings) in a safe environment.
Evidence base: VR used to study eating disorders, anxiety/phobias, PTSD, autism, dementia, and psychosis; VR as exposure therapy; safety and efficacy generally positive but diverse study sizes.
Common phobic exposure targets: heights, spiders, needles, flying; VR allows controlled, graded exposure and the option to add contextual cues (odors, sounds).
Eating disorders: VR used for body-image distortions and exposure to food contexts (kitchens, cafés); augmentation with olfactory cues.
PTSD: VR-based simulations (war-zone re-experiencing contexts) for therapy; prevention studies addressing resilience before exposure.
Psychosis: VR used to explore paranoid ideation and social avoidance; potential to train social interactions and coping strategies.
Challenges and safety: cyber-sickness (simulator sickness) with older equipment; modern headsets reduce risk; monitor for adverse effects.
Other considerations: data privacy, self-administration vs clinician-guided use; ethical approvals; potential for self-help products lacking guidance.
Case studies and media references: VR in education and clinical training; public dissemination through media.
Topic 2 — VR and neuropsychological measures
Neuropsychology aims: link brain function to cognitive processes; traditional tests may lack ecological validity.
VR advantages: dynamic, immersive tasks mimic real-world cognitive demands; flexible control of distractors and task load; potential for standardised yet ecologically valid assessment.
Limitations: VR tasks can be more complex, requiring more cognitive resources; simulator sickness persists in some populations; variability in hardware/software across clinics.
Neuropsychological functions assessed via VR: executive function, attention, inhibition, memory, visuospatial abilities; examples include spatial working memory tasks, and VR-based shopping tasks (VEGS).
CANTAB as a comparison: computer-based battery widely used; VR can extend to more naturalistic tasks.
Part 2 — VR and social cognition
Social cognition research with VR: use of virtual avatars to study emotion perception, social interaction, and theory of mind (ToM).
VAMA: Virtual Assessment of Mentalising Ability; tests cognitive ToM and effective ToM (emotion understanding) via interactive VR scenarios.
Benefits: high ecological validity, controlled social cues, same scenario for all participants; adverse reactions or anxiety can be monitored.
Applications to autism and psychosis: more realistic social interactions; better sensitivity to social cognitive deficits than traditional tests.
VR for attention and everyday functioning: virtual classrooms, grocery stores (VEGS), and realistic social scenarios to measure attention, distractibility, and goal-directed behaviour.
Virtual social cognition in adolescents: school canteen scenario to study anxiety and social acceptance; early data link negative beliefs to loneliness and generalized anxiety; potential for intervention development.
Topic 3 — Pros, challenges, and ethics of VR in mental health (Part 3)
Benefits: personalised, scalable, engaging; can bridge research and clinical practice; potential to augment training of staff and patient education.
Challenges: data privacy, safeguarding; need for robust randomized controlled trials to establish efficacy; integration with real-world settings; cost and accessibility barriers.
Future directions: combining VR with physiological sensing (heart rate, GSR) and experience sampling; evaluating immersion levels (full VR vs augmented reality) and their therapeutic value.
Connections across topics and themes
The transcript emphasizes a common methodological thread: build on prior foundations (phrenology to modern localisation; lesion studies to targeted manipulations; in vitro to in vivo and human inferences).
A recurring motif is “identify, map, observe, manipulate” as core scientific steps.
Across weeks, the role of technology is central: imaging (MRI/fMRI, CT), histology, genetic tools (CRISPR and iPS), viral tracing (AAV, rabies, EnvA/ TVA), optical methods (patch clamp, optogenetics), computational models (Fourier analysis, phase space, attractors), and immersive tech (VR) to study brain function and behaviour.
Ethical considerations underpin translational work: stem cell sourcing, gene editing, neural prosthetics, and VR clinical deployment.
Key equations and concepts (LaTeX)
Neuronal action potential and frequency relations:
Period and frequency: T = ext{period},\omega = \frac{2\pi}{T},\ f = \frac{1}{T}.
Action potential as a sum of sinusoids (Fourier view): x(t) \approx \sum{k=1}^{\infty} Ak \sin(\omegak t + \phik).
Fourier transform (basic defintion): X(\omega) = \int_{-\infty}^{\infty} x(t) \mathrm{e}^{-i\omega t} dt.
Phase space and attractors (conceptual): a dynamical system state x evolves with attractor A such that trajectories converge toward A; Lorenz attractor is a prototypical chaotic attractor with the classic butterfly shape. The Lorenz equations (typical representation) are:
\frac{dx}{dt} = \sigma(y - x),
\frac{dy}{dt} = \rho x - y - x z,
\frac{dz}{dt} = x y - \beta z.Basic imaging resolution (Abbe limit in practice): resolution ~ d \approx \dfrac{\lambda}{2\,\mathrm{NA}}. For visible light (λ ≈ 500–550 nm) and high NA ≈ 1.4, d ≈ 180–200 nm.
Conceptual CRISPR editing workflows (summary): NHEJ leads to indels and gene knockout; HDR uses a repair template to introduce precise edits; PAM requirement for Cas9 is \text{PAM} = \text{NGG} for SpCas9.
Practical implications and real-world relevance
Understanding brain history helps contextualise how contemporary methods evolved from early methods to modern, non-invasive techniques.
NSCs hold promise for disease modelling and potential regenerative therapies; still require rigorous control of differentiation, stability, and immune compatibility.
CRISPR enables precise disease modelling and potential therapies but requires careful handling of off-target effects, delivery, and ethical considerations for human use.
Connectomics and advanced tracing techniques (AAV, rabies, Cre-LoxP) provide deep insights into circuit connectivity, with important implications for understanding neurodevelopmental and neurodegenerative disorders.
Computational neuroscience provides a framework to understand action selection, decision making, and network dynamics in both health and disease; cross-species comparisons (basal ganglia vs insect central complex) reveal conserved principles.
Neuroprosthetics and brain-machine interfaces illustrate the translational potential of neuroscience into clinical therapies for SCI and motor disorders, while highlighting the tech, ethical, and regulatory challenges ahead.
Sleep, inflammation, microbiota-gut-brain axis, and cancer therapies illustrate the broad landscape of factors shaping neuroplasticity and mental health, emphasizing systems-level interactions across immunology, endocrinology, and neural circuits.
Suggested study actions
Create flashcards for major historical figures and their contributions (e.g., Galvani, Loewi, Sherrington, Broca, Wernicke, Golgi, Cajal).
Draw simplified schematic diagrams linking basal ganglia components to actions (D1 direct vs D2 indirect) and annotate with functional outcomes.
Practice tracing strategies (anterograde vs retrograde; CTB, DiI, Fluoro-Gold) and their applications to connectomics questions.
Work through the CRISPR/ HDR/NHEJ workflow diagrams and understand vector packaging limits and delivery challenges.
Revisit the Fourier transform and phase-space concepts with a short example (two simulated sine waves) to visualise how complex neural signals can be decomposed and interpreted.
Summarise the pros/cons of VR in mental health and design a mini study that could test a VR-based exposure protocol for a phobia, noting ethical and safety considerations.
Quick glossary (selected terms)
Synapse: functional connection between two neurons, typically not physically touching; Sir Charles Sherrington coined the term.
Phrenology: historical theory linking skull shape to personality; ultimately discredited as a science, but catalysed localisation ideas.
Neuron doctrine: concept that the brain is made of discrete cells (neurons) that communicate via synapses.
DREADDs: designer receptors exclusively activated by designer drugs; chemogenetic control of neuronal activity.
GRASP: GFP reconstitution across synaptic partners; a method for identifying synaptic contacts.
Descartes vs monism: philosophical debate about mind-body relationship; modern neuroscience largely adopts a material (neuronal) basis for mental processes.
Cre-LoxP: genetic tool enabling cell-type-specific gene expression; enables conditional knockout/ expression.
Final thought
The course highlights that neuroscience is a continually evolving discipline, driven by technological advances and methodological innovations. The history, current tools, and ethical considerations form a framework for understanding how to translate basic science into clinical and societal benefits while navigating complex trade-offs.
Title: Comprehensive Neuroscience Notes (Week 1–5)
Week 1 — From past to future: how did neuroscience begin and where is it taking us?
Topic 1: Looking back to move forward — a brief history of neuroscience (Part 1 of 3)
Definition of neuroscience: the scientific study of the brain and the nervous system, encompassing its structure, function, development, and evolution, both in health and disease.
Levels and approaches: neuroscience employs a broad range of investigative levels, from the minuscule (molecular interactions of proteins, genes, and membranes) to the microscopic (cellular properties of neurons and glia), to the mesoscopic (synaptic transmission and neural circuit function), and macroscopic (network dynamics, computational models, and behavioural outcomes). Often, multiple levels are investigated simultaneously to gain a comprehensive understanding.
Interdisciplinarity: the history of neuroscience demonstrates a rich interplay of disciplines, including biology, psychology, medicine, physics, chemistry, and engineering, all feeding into a holistic understanding of the brain and behaviour. This interdisciplinary nature is crucial for applied neuroscience.
History linked to technology and instruments; conceptualisations tethered to cutting-edge tools. Advances in understanding often follow the invention of new methodologies (e.g., microscopy, imaging).
Early sign of brain importance observed even in prehistoric times (e.g., evidence of purposeful brain intervention in skulls through trepanation).
Trepanation: archaeological evidence from Neolithic and prehistoric skulls shows surgical holes, often with clear bone growth around the site, indicating that individuals survived the procedure for prolonged periods. Some individuals underwent multiple trepanations over their lifetime.
Theories: prominent theories suggest trepanation was performed for the removal of evil spirits or demons believed to cause mental illness, or as a physical treatment for head injuries (e.g., fractured skulls) or neurological conditions like epilepsy, severe headaches, or intracranial pressure. Modern medical parallel: the practical benefit recognized in some cases for relieving intracranial swelling after trauma or stroke.
Tools: archeological findings indicate the use of rudimentary tools, such as sharpened flint-knapped blades (e.g., obsidian) or abrasive stones, for cutting or scraping away bone. Other materials found nearby often provided clues to their use.
Contemporary claim: while not medically sanctioned, anecdotal reports suggest the existence of underground trepanation enthusiasts who reportedly practice it for purported higher consciousness or altered states. This practice is extremely dangerous and not medically recommended.
Egyptians (about 5,000+ years ago): ancient Egyptian mummification practices show limited regard for the brain, as it was typically discarded during the embalming process. Hooks were conventionally used to reach through the nasal cavity and remove brain tissue, often through liquefaction. In contrast, the heart was meticulously preserved, as it was considered the seat of the soul, consciousness, and emotion, crucial for the afterlife relevance.
Edwin Smith Surgical Papyrus (circa 1600 BCE, but reflects knowledge from ~3000-2500 BCE): regarded as the oldest surviving medical text, this papyrus details clinical observations and treatments for various injuries, particularly head trauma. It provided the first recorded descriptions of the brain, its meninges, cerebrospinal fluid, and intracranial pulsations. Notably, it observed specific clinical correlations, such as paralysis and lack of sensation in body parts resulting from nerve damage after head injuries, suggesting an early rudimentary understanding of brain-body connections. However, the text also contained debates about the precise nature of brain connections and their functional implications.
