Comprehensive Cellular, Molecular, and Systems Neuroscience

Comprehensive practice flashcards covering neurotransmitter synthesis, storage, and clearance, ionotropic and metabotropic receptor cascades, neuroanatomy, neural development, axonal guidance, synaptogenesis, and visual system neurobiology.

What is the rate-limiting step and primary enzyme in the biosynthesis of catecholamines?

The conversion of Tyrosine to L-Dihydroxyphenylalanine (L-DOPA), catalyzed by the cytoplasmic enzyme tyrosine hydroxylase (TH).

Which enzyme catalyzes the conversion of glutamate into gamma-aminobutyric acid (GABA)?

Glutamate decarboxylase (GAD).

How are classic neurotransmitters actively transported into synaptic vesicles against their concentration gradient?

A vesicular $H^+$ -ATPase pumps protons into the vesicle lumen to generate an electrochemical proton gradient. Specific vesicular neurotransmitter transporters then utilize this proton gradient to drive neurotransmitter uptake into the vesicle.

What are the four primary mechanisms responsible for removing neurotransmitters from the synaptic cleft?

1. Simple diffusion away from the synaptic cleft
2. Enzymatic degradation within the cleft (e.g., acetylcholinesterase cleaving ACh into choline and acetate)
3. Uptake into surrounding glial cells (e.g., glutamate uptake by astrocytes via EAATs)
4. Reuptake into the presynaptic terminal via sodium-dependent transporters (e.g., SERT, DAT)

How do neuropeptides differ from classic small-molecule neurotransmitters in their site of synthesis and conditions required for synaptic release?

Neuropeptides are synthesized as precursor proteins (preproneuropeptides) on ribosomes of the rough ER in the soma, processed through the Golgi apparatus, packaged into large dense-core vesicles (70–250 nm), and transported down the axon via kinesin along microtubules. Unlike classic transmitters that release with single action potentials, neuropeptides require high-frequency stimulation that creates a diffuse intracellular $Ca^{2+}$ elevation throughout the terminal.

How is nitric oxide (NO) synthesized, and how does it act as a non-classic neurotransmitter?

Nitric oxide is synthesized on demand from arginine by the enzyme nitric oxide synthase (NOS). Because it is a gas, it is not packaged into vesicles, has no membrane-bound receptor, and diffuses directly across cell membranes to act on targets in adjacent cells.

How do the subunit stoichiometry and transmembrane topologies differ among ionotropic glutamate receptors, Cys-loop receptors (ACh, GABA-A, glycine), and purine (P2X) receptors?

• Glutamate receptors (AMPA, NMDA, Kainate): 4 subunits around a pore, each containing 3 transmembrane domains (M1, M3, M4) and a re-entrant pore loop (M2).
• Cys-loop receptors (Nicotinic ACh, $5\text{-HT}_3$, $\text{GABA}_A$, Glycine): 5 subunits around a pore, each containing 4 transmembrane domains (M1–M4).
• Purine P2X receptors: 3 subunits around a pore, each containing 2 transmembrane domains (M1, M2).

What two physiological requirements must be met simultaneously for NMDA receptors to conduct $Ca^{2+}$ into the postsynaptic cell?

1. Co-agonist binding: Both glutamate and glycine must bind to their respective subunit sites.
2. Membrane depolarization: Depolarization of the postsynaptic membrane (typically supplied by sodium influx through adjacent AMPA receptors) is required to expel the voltage-dependent $Mg^{2+}$ ion blocking the channel pore.

What is the sequence of events during retrograde endocannabinoid signaling at a synapse?

1. Postsynaptic depolarization causes an influx of $Ca^{2+}$, stimulating on-demand synthesis of endocannabinoids (2-AG or anandamide).
2. These lipid messengers diffuse retrogradely across the plasma membrane and synaptic cleft.
3. Endocannabinoids bind to presynaptic $CB_1$ G-protein coupled receptors.
4. Activated $CB_1$ receptors inhibit presynaptic voltage-gated $Ca^{2+}$ channels, suppressing further neurotransmitter release (either glutamate or GABA).

How do norepinephrine and acetylcholine produce opposing effects on cardiac pacemaker cells via GPCR signaling?

• Norepinephrine binds $\beta_1$-adrenergic receptors, activating $G_s$. $G\alpha_s\text{-GTP}$ stimulates adenylyl cyclase (AC) to convert ATP to cAMP, activating PKA and opening HCN pacemaker channels and voltage-gated $Ca^{2+}$ channels to increase heart rate and contractility.
• Acetylcholine binds $M_2$ muscarinic receptors, activating $G_i$. $G\alpha_i$ inhibits adenylyl cyclase (lowering cAMP), while liberated $G\beta\gamma$ subunits directly open inward rectifying GIRK ($K^+$) channels, causing hyperpolarization that slows heart rate.

What second messengers are generated by the $G_q$ / Phospholipase C (PLC) cascade, and what are their downstream actions?

Activated $G\alpha_q\text{-GTP}$ activates PLC, which cleaves phosphatidylinositol 4,5-bisphosphate ($\text{PIP}_2$) into:

• Inositol 1,4,5-trisphosphate ($\text{IP}_3$): Diffuses to the smooth endoplasmic reticulum, binding ligand-gated $\text{IP}_3$ receptors to release stored $Ca^{2+}$, activating calmodulin and CaM kinase.
• Diacylglycerol (DAG): Remains embedded in the membrane and, in synergy with released $Ca^{2+}$, activates Protein Kinase C (PKC) to phosphorylate substrate proteins.

What intracellular pathway mediates gene transcription downstream of neurotrophin binding to a Trk receptor tyrosine kinase?

Neurotrophin binding triggers Trk dimerization and autophosphorylation on cytoplasmic tyrosine residues. Adaptor proteins (e.g., Shc, Grb2, SOS) recruit Ras, exchanging GDP for GTP. Ras-GTP activates the protein kinase cascade: Raf (MAPKKK) $\rightarrow$ MEK1/2 (MAPKK) $\rightarrow$ MAPK/ERK (MAPK), which translocates to the nucleus to phosphorylate transcription factors that promote cell differentiation and survival.

How do converging intracellular signaling pathways lead to CREB phosphorylation and altered gene expression?

Elevated cAMP (activating PKA), intracellular $Ca^{2+}$ influx (activating CaMKIV), and receptor tyrosine kinase signaling (activating RSK via MAPK) converge on the transcription factor CREB (cAMP response element-binding protein). These kinases phosphorylate CREB, causing it to dimerize and bind to cAMP response elements (CREs) on DNA, stimulating transcription of genes essential for synaptic plasticity, such as BDNF, GluR1, and tyrosine hydroxylase (TH).

Identify the three primary embryonic brain vesicles shown and name one mature adult brain structure derived from each.

1. Prosencephalon (forebrain): Gives rise to the telencephalon (cerebral cortex, hippocampus, basal ganglia) and diencephalon (thalamus, hypothalamus).
2. Mesencephalon (midbrain): Gives rise to the tectum (superior and inferior colliculi), red nucleus, and substantia nigra.
3. Rhombencephalon (hindbrain): Gives rise to the metencephalon (pons, cerebellum) and myelencephalon (medulla oblongata).

What are the three cranial and spinal meninges from superficial to deep, and where does cerebrospinal fluid (CSF) circulate?

From superficial to deep:

1. Dura mater: Thick, fibrous protective membrane adhering to bone.
2. Arachnoid mater: Spiderweb-like middle layer; arachnoid villi reabsorb CSF into the superior sagittal sinus.
3. Pia mater: Delicate, one-cell-thick membrane directly coating brain and spinal cord contours. CSF circulates within the subarachnoid space between the arachnoid mater and the pia mater.

How does the 'birthday' of a progenitor cell dictate its layer destination and phenotypic fate during cortical development?

Neocortical development follows an 'inside-out' laminar migration pattern. Early-born neurons migrate from the ventricular zone to settle in the deepest cortical layers (e.g., Layer VI and subplate). Later-born neurons migrate past older layers along radial glia to settle in progressively more superficial layers (Layers V, IV, and II/III). Early embryonic stages are neurogenic (producing neurons), whereas later stages undergo a fate switch to gliogenesis, generating astrocytes first and oligodendrocytes last.

How does Sonic Hedgehog (Shh) establish distinct neuronal subtype domains in the ventral spinal cord?

Shh is secreted by the notochord and ventral floor plate, creating a ventral-high to dorsal-low concentration gradient. Shh acts in a threshold-dependent manner to repress Class I transcription factors (Pax7, Dbx1, Dbx2, Irx3, Pax6) and activate Class II transcription factors (Nkx6.1, Nkx2.2). Cross-repressive interactions between pairs (such as Dbx2 vs. Nkx6.1, and Pax6 vs. Nkx2.2) sharpen boundaries to define five distinct progenitor domains (p0, p1, p2, pMN, p3), which differentiate into V0–V3 interneurons and motor neurons (MN).

What morphogens establish the rostral-caudal patterning axis of the neural tube?

• Anterior/Rostral: Fibroblast growth factors (FGFs), which promote Pax6 and suppress Emx2 expression.
• Posterior/Caudal: Bone morphogenetic proteins (BMPs), Wnts, and Retinoic Acid (RA). Retinoic acid acts as a caudalizing morphogen that induces nested expression of the Hox gene transcription factor family along the spinal cord.

How do LIM homeodomain transcription factors and Eph/ephrin interactions direct motor axon projections into limb musculature?

• Medial motor column neurons express the transcription factor Isl1, which upregulates EphB receptors; ephrin-B concentrated in the dorsal limb mesenchyme repels these axons, directing them ventrally.
• Lateral motor column neurons express Lim1, which upregulates EphA4 receptors; ephrin-A concentrated in the ventral limb mesenchyme repels these axons, directing them dorsally.

How do guidance cues guide commissural axons to cross the ventral midline and then prevent them from recrossing?

1. Approach: Ventral floor plate Netrin diffuses in a gradient, attracting the axonal growth cone via DCC receptors.
2. Midline crossing: Slit at the midline is repulsive to Robo receptors, but the protein Comm prevents Robo from reaching the growth cone surface, keeping the axon insensitive to Slit.
3. Preventing recrossing: Once across the midline, Comm is downregulated and Robo returns to the surface. Slit binds Robo to repel the axon away from the midline; internalized Robo also physically binds and inactivates DCC, silencing Netrin attraction.
4. Rostral turn: Wnt4 attracts the axon rostrally toward the brain via Frizzled3 receptors.

What reciprocal organizer functions do neurexin and neuroligin perform during synaptogenesis?

• Presynaptic neurexin triggers the postsynaptic membrane to assemble postsynaptic density scaffolding proteins (e.g., PSD-95 or gephyrin) and cluster neurotransmitter receptors (AMPA/NMDA or $\text{GABA}_A$).
• Postsynaptic neuroligin signals retrogradely to the presynaptic terminal to induce active zone assembly and synaptic vesicle clustering.

How do neurofascin and ankyrin-G guide the subcellular innervation of Purkinje cells by cerebellar basket cells?

The cell adhesion molecule neurofascin is localized at high concentrations to the axon initial segment (AIS/axon hillock) of Purkinje cells, anchored there by the cytoskeletal scaffolding protein ankyrin-G. Cerebellar basket cell axons recognize neurofascin as an attractive target. In $Ankg^{-/-}$ mutants lacking ankyrin-G, neurofascin fails to localize to the AIS, causing basket cell axons to form aberrant synapses diffusely across the Purkinje soma.

Identify the cellular layers and direct pathway of visual information transmission depicted in this retinal cross-section.

Light travels through the inner layers to reach the photoreceptors at the back. The direct through-pathway consists of: Photoreceptor (rod or cone) $\rightarrow$ Bipolar cell $\rightarrow$ Retinal ganglion cell (RGC), whose axons form the optic nerve. Lateral processing is mediated by horizontal cells (in the outer plexiform layer) and amacrine cells (in the inner plexiform layer); Müller cells provide glial support.

What maintains the 'dark current' and resting depolarization of rod photoreceptors in absence of light?

In darkness, guanylyl cyclase continuously synthesizes cyclic guanosine monophosphate (cGMP) from GTP. cGMP binds to cyclic nucleotide-gated (CNG) cation channels, keeping them open. Influx of $Na^+$ and $Ca^{2+}$ through CNG channels maintains the photoreceptor in a partially depolarized state ($\sim -30\text{ mV}$), driving continuous tonic release of glutamate.

What molecular signaling cascade occurs in a rod photoreceptor following photon absorption?

1. A photon isomerizes 11-cis-retinal into all-trans-retinal within rhodopsin.
2. Opsins undergo a conformational shift to metarhodopsin II.
3. Rhodopsin activates the heterotrimeric G-protein transducin ($G_t$), exchanging GDP for GTP on $G\alpha_t$.
4. $G\alpha_t\text{-GTP}$ activates cGMP phosphodiesterase (PDE).
5. PDE rapidly hydrolyzes cGMP into 5'-GMP.
6. Falling cGMP levels cause CNG cation channels to close.
7. Blockade of inward $Na^+$ and $Ca^{2+}$ current hyperpolarizes the membrane (toward $-60\text{ mV}$), closing terminal voltage-gated $Ca^{2+}$ channels and decreasing glutamate release.

What molecular mechanisms extinguish activated rhodopsin and restore the rod photoreceptor to its dark state during recovery?

1. Rhodopsin kinase (GRK1) phosphorylates activated opsin, allowing arrestin to bind and block further transducin activation.
2. Transducin's intrinsic GTPase activity (accelerated by RGS9) hydrolyzes GTP to GDP, releasing and inactivating PDE.
3. CNG channel closure decreases intracellular $Ca^{2+}$, releasing inhibition on guanylyl cyclase-activating proteins (GCAPs).
4. GCAPs stimulate guanylyl cyclase to produce new cGMP from GTP, reopening CNG channels to restore the depolarizing dark current.
5. All-trans-retinal dissociates from opsin and is converted back to 11-cis-retinal in the retinal pigment epithelium (RPE).

How do rods and cones differ across photopigments, retinal distribution, sensitivity, response speed, and light adaptation?

• Photopigments: Rods contain 1 photopigment (rhodopsin); cones contain 3 opsin subtypes (S/blue, M/green, L/red).
• Distribution: Rods are distributed in the peripheral retina and absent from the central fovea; cones are concentrated in the central retina and fovea.
• Sensitivity: Rods are highly sensitive to single photons (scotopic/night vision); cones have low light sensitivity (photopic/day vision).
• Speed & Recovery: Rods have slow response kinetics and slow recovery; cones have fast response kinetics and rapid recovery (high temporal resolution).
• Light Adaptation: Rods saturate at moderate light levels; cones adapt dynamically across bright light.

Why is visual acuity highest at the fovea, whereas central color vision ceases in pitch-black darkness?

The fovea contains exclusively densely packed cones with minimal receptive field convergence (representing $1\%$ of retinal area but supplying $50\%$ of optic nerve fibers) and lateral displacement of inner cell layers, giving maximum visual acuity in daylight. However, because the central fovea contains zero rods and cones have low light sensitivity, central vision cannot detect stimuli in pitch darkness.

Why does a light-induced drop in photoreceptor glutamate release produce opposite responses in ON-center and OFF-center bipolar cells?

• ON-center bipolar cells express metabotropic mGluR6 receptors: In darkness, glutamate binding to mGluR6 closes cation (TRPM1) channels, hyperpolarizing the cell. In light, the decrease in glutamate relieves this inhibition, allowing cation channels to open, which depolarizes the ON bipolar cell.
• OFF-center bipolar cells express ionotropic AMPA/kainate receptors: In darkness, glutamate opens cation channels, depolarizing the cell. In light, decreased glutamate reduces channel opening, which hyperpolarizes the OFF bipolar cell.

How do horizontal cells generate lateral inhibition in retinal center-surround receptive fields?

When light shines in the surround of a receptive field, surround photoreceptors hyperpolarize and release less glutamate onto horizontal cells. This reduces horizontal cell excitation, causing them to decrease inhibitory GABA release onto the center photoreceptor terminal (or directly onto bipolar cells). This disinhibition modulates glutamate release, accentuating the contrast difference between the center and surround.

How do parvocellular (P) and magnocellular (M) retinal ganglion cells differ functionally and anatomically?

• Parvocellular (P) cells: Small cell bodies with small, compact dendritic trees and small receptive fields; slow axonal conduction; exhibit sustained firing; code fine spatial detail, high visual acuity, shape, and color opponency (red-green, blue-yellow).
• Magnocellular (M) cells: Large cell bodies with extensive dendritic trees and large receptive fields; fast axonal conduction; exhibit transient burst firing; lack color opponency; specialize in detecting motion, flicker, and low-contrast stimuli.

How does visual field information decussate at the optic chiasm to create contralateral hemispheric representations?

Axons from the nasal hemiretina cross the midline at the optic chiasm, whereas axons from the temporal hemiretina remain uncrossed (ipsilateral). Because the left visual hemifield projects onto the nasal retina of the left eye and the temporal retina of the right eye, all left-visual-field inputs travel into the right optic tract, projecting to the right lateral geniculate nucleus (LGN) and right primary visual cortex.

Based on this visual field defect map, identify the lesions that produce: (1) monocular blindness, (2) bitemporal hemianopia, and (3) homonymous hemianopia.

1. Monocular blindness (deficit 1): Complete transection of the optic nerve on that side (e.g., right optic nerve cut eliminates all input from the right eye).
2. Bitemporal hemianopia (deficit 2): Midline lesion of the optic chiasm (e.g., pituitary tumor compressing crossing nasal hemiretinal fibers, abolishing temporal peripheral fields in both eyes).
3. Homonymous hemianopia (deficit 3): Complete transection of the optic tract (e.g., right optic tract cut eliminates input from the left visual hemifield in both eyes).

What is the structural organization of eye input and cell types across the 6 layers of the Lateral Geniculate Nucleus (LGN)?

• Eye-specific inputs: Layers 1, 4, and 6 receive input from the contralateral eye (crossing nasal fibers); Layers 2, 3, and 5 receive input from the ipsilateral eye (uncrossed temporal fibers).
• Cell pathways: Layers 1 and 2 are magnocellular layers (large cells, fast conducting, motion/depth); Layers 3, 4, 5, and 6 are parvocellular layers (small cells, sustained firing, color/form).
• Koniocellular neurons are distributed between the principal layers and receive non-M, non-P inputs.

What is the canonical laminar circuit of sensory information through primary visual cortex (V1 / Brodmann area 17)?

LGN thalamic axons terminate primarily in Layer IV of V1 (magnocellular inputs target layer $IVC\alpha$, parvocellular target layer $IVC\beta$). Layer IV neurons project vertically to Layers II and III. Layers II/III send intracortical outputs to other areas (such as V2) and project down to Layer V (which outputs subcortically to the superior colliculus and pons) and Layer VI (which sends reciprocal feedback to the LGN and Layer IV).

How do receptive field properties and stimulus requirements differ between simple cells and complex cells in V1?

• Simple cells: Receptive fields have distinct, segregated ON and OFF subregions arranged in parallel. They respond maximally to a stationary bar or edge of light at a specific orientation and specific position, constructed from convergent inputs of aligned center-surround LGN neurons.
• Complex cells: Receptive fields are larger without distinct ON/OFF subdivisions. They respond to an oriented bar anywhere within the field and typically exhibit direction selectivity (firing to oriented edges sweeping in a preferred direction), constructed from convergent inputs of multiple simple cells.

What three columnar architectures integrate to form a functional visual cortical module in V1?

1. Ocular dominance columns: Alternating cortical bands ($\sim 0.5\text{ mm}$ wide) spanning all layers that preferentially process input from either the left or the right eye.
2. Orientation columns: Vertical slabs whose neurons share identical preferred orientation angles, shifting smoothly in pinwheel patterns across the cortical surface.
3. Cytochrome oxidase blobs: Cylindrical pillars in layers II and III rich in cytochrome oxidase that lack orientation tuning and process wavelength/color information.

What are the anatomical routes and functional specializations of the dorsal ('where') and ventral ('what') visual processing streams beyond V1?

• Dorsal stream ('where' or 'how'): Originates primarily from magnocellular inputs, travels from V1 through V2 and V3/V3a to area MT (V5) and the posterior parietal cortex; specializes in motion detection, spatial depth perception, and visual guidance of motor action.
• Ventral stream ('what'): Receives both parvocellular and magnocellular inputs, travels from V1 through V2 to area V4 and the inferior temporal cortex (IT); specializes in high-resolution form analysis, color processing, surface properties, and object/face recognition.