Integrative Study of

Neural Systems and Behavior

Hans A. Hofmann

The University of Texas at Austin

Center for Computational Biology and Bioinformatics

Department of Integrative Biology

Institute for Cellular & Molecular Biology

Institute for Neuroscience

hans@utexas.edu

http://cichlid.biosci.utexas.edu/

Could a neuroscientist understand a microprocessor?

Jonas & Kording, 2016

(1) There exist complex information-processing systems which are composed of many interconnected discrete "units“

(2) For all their differences, brains and microprocessors are examples of such systems

(3) We need analytical and measurement techniques to understand these systems

(4) Neuroscientists have come up with many such approaches

(5) If these approaches are useful at figuring out the systems described in (1), then they ought to be informative when applied to any of those systems

We Actually Understand the MOS 6502 Processor

Jonas & Kording, 2016

Behavioral Phenotypes of a Microprocessor MOS 6502

Jonas & Kording, 2016

Jonas & Kording, 2016

Reconstructing the Connectome

Jonas & Kording, 2016

Lesioning Transistors to Understand Function

Jonas & Kording, 2016

Spike Statistics

Jonas & Kording, 2016

Quantifying Tuning Curves to Understand Function

Jonas & Kording, 2016

Measuring Local Field Potentials to Understand Network Properties

Jonas & Kording, 2016

Understanding Functional Connectivity

Jonas & Kording, 2016

Whole Brain Recording to Obtain ALL the Data!

Integrative Study of Neural Systems & Behavior

Core Competencies* Example Application

quantification of behavior

field methods, behavioral observations, natural history

knowing your animal, ethograms

ecology/evolution ultimate causes, environmental determinants of behavior, measuring fitness

putting research questions in broader biological context

mathematical theory game theory, evolutionary simulations

process based models of evolutionary and behavioral dynamics

statistics Bayesian analysis hierarchical models

computational methods bioinformatics, machine learning tracking, feature extraction, handling genomic data

genetics/genomics functional genomics, gene expression

genotyping, gene function, gene manipulation

physiology/neurobiology endocrinology, electrophysiology characterizing neural/molecular mechanism

Table 1. Core competencies for the integrative study of NS&B.

http://www.nsf.gov/div/index.jsp?div=IOS

http://www.slideshare.net/mmehlmann/blind-menelephant

The Blind Men and the Elephant

It was six men of Indostan

To learning much inclined,

Who went to see the Elephant

(Though all of them were blind),

That each by observation

Might satisfy his mind

[…]

So oft in theologic wars,

The disputants, I ween,

Rail on in utter ignorance

Of what each other mean,

And prate about an Elephant

Not one of them has seen!

John Godfrey Saxe (1816–1887)

If each had a candle and they went in

together the differences would disappear.

Rumi, 13th Century Persian poet and Sufi teacher

-Integrating multiple technologies

-Meta-analyses of large-scale (public) data sets

-Working across disciplines

-Large-scale collaborations and/or centers

-…

What IS the “Integrative” Study of Brain and Behavior?

Practical Considerations

-Pursuing two or more of “Tinbergen's Four Questions” in the same study

-Integrating across levels of biological organization

-Integrating across time scales

-Using a comparative/phylogenetic approach

-…

What IS the “Integrative” Study of Brain and Behavior?

Conceptual Approaches

Function

Causation

Development

Evolution

Four Fundamental Questions of Biological Research

Niko Tinbergen

1973 Nobel Prize

“Tinbergen’s Four

Questions” (1963)

-Pursuing two or more of “Tinbergen's Four Questions” in the same study

-Integrating across levels of biological organization

-Integrating across time scales

-Using a comparative/phylogenetic approach

-…

What IS the “Integrative” Study of Brain and Behavior?

Conceptual Approaches

Gene Expression

Neural Circuits

Social Networks

Evolution

Integrating Across Levels of Biological Organization

-Pursuing two or more of “Tinbergen's Four Questions” in the same study

-Integrating across levels of biological organization

-Integrating across time scales

-Using a comparative/phylogenetic approach

-…

What IS the “Integrative” Study of Brain and Behavior?

Conceptual Approaches

Integration Across Time ScalesE

nvir

onm

ent/

Ph

eno

typ

e Modulation

Learning & Memory Formation

Generation S Generation XGeneration L Generation XL

“Epigenetic Plasticity”

Genomic imprinting

Maternal effects

Behavioral imprinting

Social learning/traditions

(Adaptive) Phenotypic Plasticity

Passive or active

Irreversible: Developmental Plasticity,

Polyphenisms

Reversible: Use-dependent changes, Memory,

Traits under behavioral/environmental control

Genetic Polymorphisms

Evolutionary Plasticity

Mutation

Selection & DriftTime

-Pursuing two or more of “Tinbergen's Four Questions” in the same study

-Integrating across levels of biological organization

-Integrating across time scales

-Using a comparative/phylogenetic approach

-…

What IS the “Integrative” Study of Brain and Behavior?

Conceptual Approaches

The Power of the Comparative Method

"Ought we, for instance, to begin by discussing each separate species - man,

lion, ox, and the like - taking each kind in hand independently of the rest, or

ought we rather to deal first with the attributes which they have in common in

virtue of some common element of their nature, and proceed from this as a

basis for the consideration of them separately?“Aristotle, Περὶ ζῴων μορίων, ca. 350 BC

"... we must learn to treat comparative data with the same respect as we would

treat experimental results ...“Maynard Smith & Holliday, 1979

Aristotle (384-322)

John Maynard Smith

(1920-2004)

25

Using a Comparative/Phylogenetic Approach

Pollen AA & Hofmann HA, 2008, Brain, Behavior & Evolution 72:145

19th Century Physiology: Comparative in Search of Generality

Logan CA (2002) J Hist Biol 35:329–363

Journal Pflügers Archiv du Bois Archiv

1885-1900: volumes, papers 45, 931 16, 402

Single species papers 64.6% 64.6%

Humans 24.4% 15.4%

Dogs 13% 19.1%

Rabbits 5.2% 6%

Frogs 12% 15.2%

Other 10% 8%

Multi-species papers 32% 33.6%

2 species >14% >17.2%

≥3 species ~18% ~16.4%

Species/volume 3-10 (mode = 6) 4-9 (mode = 6)

New species encounter rate 3.5 papers 4.5 papers

What is a Model System?

From Wikipedia, the free encyclopedia

A model organism is a non-human species that is extensively studied to understand

particular biological phenomena, with the expectation that discoveries made in the organism model will

provide insight into the workings of other organisms.Model organisms are in vivo models and are widely used

to research human disease when human experimentation would be unfeasible or unethical. This strategy is

made possible by the common descent of all living organisms, and the conservation of metabolic and

developmental pathways and genetic material over the course of evolution.Studying model organisms can be

informative, but care must be taken when extrapolating from one organism to another.http://en.wikipedia.org/wiki/Model_organism

Krogh’s Principle: Assumes Generality!

“For a large number of problems there will be some animal of choice, or a few such animals, on which it can be most conveniently studied.”

August Krogh (1874-1949)

Nobel Prize in Physiology

or Medicine 1920

Krogh A (1929) Science 70:200–204

Lewis Carroll: The Hunting of the Snark

Lewis Carroll (1832 –

1898)

Lewis Carroll, 1879

“If your Snark be a Snark, that is right:

Fetch it home by all means—you may serve it with greens,

And it's handy for striking a light.

*******************

"But oh, beamish nephew, beware of the day,

If your Snark be a Boojum! For then

You will softly and suddenly vanish away,

And never be met with again!'”

Frank Beach: The Snark is a Boojum!

Frank A. Beach (1911-

1988)

Founder of Behavioral

Neuroendocrinology

Beach FA. 1950. American Psychologist 5:115–124.

Disparity in the Organisms Used in Studies of Social Behavior, Ecology, and Neurobiology

Taborsky, Hofmann et al. (2015) TINS 38:189-191

Utilizing Many Systems Within a Comparative Framework

Phelps SM, Campbell P, Zheng D, Ophir AG. 2010.

Neuropharmacology 58:17–28.

Benefits:

- No single species is suitable to address all aspects of a question or (human) phenotype of interest

- Focus on a small number of distantly related species makes it impossible to generalize

- Evolutionary approaches and non-traditional models can illuminate the nature and origin of within-species variation

http://www.slideshare.net/mmehlmann/blind-menelephant