Comprehensive History and Foundations of Neuroscience

The Maturation of the Field: The Age of Neurons, Synapses, and Circuits

• Definition of the Mature Field: This historical period marks when neuroscience became an independent discipline, distinct from psychology, medicine, or other fields that historically studied the brain.
• Defining Elements: This era is characterized by the discovery and definition of the fundamental building blocks of the brain: neurons, synapses, and circuits.
• Primary Timeline: The foundational work in this period occurred roughly between the $1880s$ and $1910$.

Santiago Ramon y Cajal: The Founder of Modern Neuroscience

• Role and Impact: Santiago Ramon y Cajal is globally recognized by neuroscientists as the founder of modern neuroscience. Working primarily in Spain (between Barcelona and Madrid), he provided the hard evidence and arguments necessary to establish the neuron as the fundamental unit of the nervous system.
• Individual Cell Theory vs. Reticulum Theory:
  • Reticulum Theory: The prevailing belief during Cajal's time was that the brain consisted of fused networks of cells that formed a continuous structure, known as a reticulum.
  • Neuron Theory: Cajal argued that neurons are individual, discrete cells that do not fuse with one another. He famously suggested that if researchers saw a reticulum, it was a result of their microscopes not working correctly.
• Major Publication: Cajal's most famous work is Texture of the Nervous System in Humans and Vertebrates.
  • Originally published in Spanish.
  • The French translation, released approximately $10$ years later at the turn of the $20th$ century, is the most famous translation.
  • The work is a huge collection consisting of three specific tomes and approximately $2,000$ pages.
• Recognition: Cajal was awarded one of the first Nobel Prizes in history ($1906$) for his discovery that the brain is made of individual cells like the rest of the body.

Scientific Lineage and Academic Tracking

• NeuroTree: A specific scientific genealogy website where researchers track their "scientific family" based on who trained whom.
  • UCLA Connection: Santiago Ramon y Cajal trained Rafael Lorenzo Vino in Spain, who later worked at Brancassello University in New York. Vino trained Vicente Al Rubia, who became a professor at UCLA. Al Rubia trained UCLA faculty members Larry Hoffmann and Ivan Lopez.
• Academic Tree: The website academictree.org hosts lineages for various fields, including history, philosophy, literature, music, and law.

Charles Sherrington and the Discovery of the Synapse

• Inference of Connection: Working in England, Charles Sherrington was a colleague of Cajal. While Cajal established that neurons were separate, Sherrington inferred how they communicated without fusing.
• The Term "Synapse": Sherrington coined the term "synapse" to describe the connection point between neurons.
• Timeline of Visualization: Sherrington made these inferences in the early $20th$ century, but the technology to actually see a synapse did not exist until the development of the electron microscope after World War II in the early $1950s$.
• Synaptic Importance: Synapses are critical because they define brain function. Most drugs affect the brain at the synaptic level, and synaptic plasticity is a primary area of study.

Horace Nagun and the Reticular Formation

• Discovery: Horace Nagun identified the reticular formation in the brain stem.
• Function: The reticular formation modulates arousal and alertness. It is essential for transitions between the awake state (high arousal, paying attention to the world) and the sleepy state (low arousal).
• Research and UCLA Legacy:
  • Initial experiments were conducted on cats.
  • Nagun was brought to UCLA in the $1950s$ and founded the Department of Anatomy, which later became Neurobiology.
  • He founded the Brain Research Institute at UCLA, which has existed for approximately $80\,\text{years}$.

Alan Hodgkin and Andrew Huxley: The Action Potential

• Discovery: In the early $1950s$, these English scientists provided the first recording and mathematical definition of the action potential.
• Experimental Subject: They used the giant axons of the squid. Invertebrates tend to have larger neurons than vertebrates, and squid axons are exceptionally large because they are formed by the fusion of smaller axons.
• The Hodgkin and Huxley Equation: They defined the electrical trace of the action potential mathematically, which remains a core requirement for neuroscience majors.
• Nobel Prize: They received the Nobel Prize because the action potential is the "bread and butter" of how information is transmitted between cells.

Bernhard Katz: Quantal Release and Neurotransmitters

• Vesicular Packaging: In the $1950s$, Bernhard Katz discovered that neurotransmitters are released in discrete packets rather than in random or continuous amounts.
• Evidence for Quanta: During experiments, Katz recorded electrical humps representing neurotransmitter release. He found that these humps occurred in specific sizes (one packet, two packets, etc.) with no in-between values.
• Definitions: At the time, these were called “quanta”; they are now known to be stored in spherical organelles called vesicles.

Brenda Milner: Memory and the Hippocampus

• Memory Acquisition: Milner discovered that the hippocampus is critical for acquiring new memories.
• Categorization of Memory: She helped divide memory into distinct categories, such as semantic memory versus procedural memory.
• Patient H.M. (Henry Molaison):
  • Milner studied this patient for over $50$ years after he lost hippocampal function.
  • The patient could remember his past but was unable to form any new memories.
  • His brain was sectioned and photographed after his death and is available at patienthn.org.

Rita Levi Montalcini: Neural Development and Nerve Growth Factor ($NGF$)

• Discovery of Growth Signals: Spanning work from the $1940s$ to the $1980s$, she discovered Nerve Growth Factor ($NGF$), a small protein that promotes the survival and growth of neurons.
• Experimental Subject: She did her primary work in chick embryos.
• Nobel Prize: She received the award in the $1986$ for identifying the signals that allow neural progenitor cells to differentiate and grow into mature, post-mitotic neurons.

Modern Times: Molecular Neurobiology and Imaging

• Modern Era (Last 30–35 Years): This period is defined by technology that allows for non-invasive study and molecular manipulation.
• PET Scanning (1970s): Developed by Michael Phelps and Edward Hoffman at UCLA.
  • Requires a radioactive tracer.
  • Useful for identifying structural changes, such as the shrinking of the striatum in Parkinson’s disease.
• Functional MRI (1990): Discovered by Seiji Ogawa.
  • The transcript refers to this as $sMRI$ (distinguishing it from structural MRI).
  • Based on blood flow changes: active brain regions require more oxygen and energy, increasing blood flow.
  • Non-invasive; does not require radioactive materials.

Eric Kendall: The Molecular Basis of Memory

• Sea Slug Research: Eric Kendall used the sea slug Aplysia californica to study the physical and chemical changes that occur in synapses when a memory is formed.
• Nobel Prize: Awarded in $2000$ for discovering the molecular basis of learning and memory.
• Personal Detail: Kendall is famously known for always wearing a bow tie.

Larry Zapersky: Circuit Formation and Molecular Identification

• UCLA Research: Larry Zapersky has been at UCLA since $1988$.
• Circuit Guidance: He studies how neurons know which specific targets to connect with. In $2000$, he discovered a gene that can produce thousands of versions of a protein that act like "ID cards" on the surface of neurons to allow for mutual recognition.

Current Research: David Glanzman and Susumo Tonegawa

• Susumo Tonegawa: Originally a Nobel-winning immunologist, he switched to neuroscience at MIT. He famously created false memories in mice and researches memory storage locations.
• David Glanzman: A UCLA researcher and student of Eric Kendall.
  • 2018 Study: Conducted an experiment where memory was allegedly introduced into an animal by injecting RNA. This paper will be the focus of the Week 5 curriculum in this course.

Student Questions and Discussion

• Question: How physically harmful to the brain are neurotoxins like alcohol?
  • Response: Low levels of alcohol are not considered neurotoxins because they don't harm the structure permanently; alcohol is a drug that alters function temporarily until it clears the system.
• Question: Can we read brain activity to recreate memories?
  • Response: Scientists can provide environmental input (sight, sound) and try to predict what was seen based on activity, but recreating internal states (like an old memory of a game) is something currently out of reach.
• Question: Do brain inputs differ by individual?
  • Response: Yes, the same input (e.g., a painting) can be encoded differently, explaining differences in perceived beauty or taste.
• Question: Why are neurons all-or-none instead of varying in strength?
  • Response: This involves molecular mechanisms and the sodium-potassium pump ($Na^+/K^+$), which will be covered in upcoming lectures.
• Question: Is the brain liquid or solid?
  • Response: It is a soft solid with the consistency of gel.
• Question: When someone forgets, are connections destroyed?
  • Response: We believe the physical correlate of forgetting is the loss of synapses, though these changes are too small to be visible at a macro level.