How a Cellular Neuroscientist Thinks About Psychiatric

Disorders

June 2011

What is this?

A Hippocampal Microculture

GFAP (astrocytes)MAP2 (dendrites)VGLUT1 (vesicles)

A Major ChallengeHow do we get from here to there?

What is psychiatry?

• Psychiatry is a medical specialty concerned with disturbances of the human mind and behavior

But…what is the “mind”?

• Mind = the result of processing in parallel but integrated brain networks that allow humans to do three major things:

– Think (attention & working memory)

– Attach value to things (emotions)

– Set & pursue goals (motivation)

LeDoux, Synaptic SelfLeDoux et al.

Psychiatric Disorders

• Are brain disorders…network problems– Not “chemical imbalances”

• Reflect dysfunction in networks underlying all three spheres of the “mental trilogy”– Emotion, motivation & cognition

Example: 3 Stages of Addiction

Koob & Volkow, 2010

What happens to brain networksin psychiatric disorders?

Lessons from the hippocampus

What is the hippocampus?

• A brain region occupying a significant chunk of the medial temporal lobe

• “Archicortex” - three-layered cortex that differs from six-layered neocortex

• Reminded histologists of a sea horse (“hippocampus”) or a ram’s horn (“Ammon’s horn”)

Why the hippocampus?• Critical for declarative memory formation,

novelty detection & contextual processing• Component of default mode ICN (+ others)

• Structural changes in Dementias, Depression, Bipolar Disorder, Schizophrenia, PTSD…

• Hippocampal involvement ensures problems with cognition, emotion & motivation

• We know a lot about hippocampal biology

Sensory CtxAssoc Ctx

Prefrontal Ctx

ParahippocampalCortex

PerirhinalCortex

EntorhinalCortex

DG

CA3

CA1

Subiculum

Rhinal Cortex HippocampusNeocortex

Hippocampal Information FlowA Primer

“Where” path

“What” path

What do hippocampal sub-regions do?

• Dentate Gyrus: “autoassociative network” – Codes different components of the same memory

• Facts, Context, Novelty …what, where, when?

• CA3: “heteroassociative network” – Links one memory to another

• Item + Context = Event• Event1+ Event2 + … = Episode• Links Events to different Episodes• Codes transitive associations (A>B>C>D>E)

• CA1: “decoder” and “mismatch detector”– Converts HC representation to a cortical form

Lisman, Eichenbaum

How does the hippocampus learn?Long-term synaptic plasticity

Hippocampal Slice

Long-term potentiation (LTP)

Physiology Recording Rig

A Major ChallengeGetting from here to there?

What happens to HC in stress?Lessons from our rodent friends

• Chronic mild stress (CMS) + forced swim• Voltage-sensitive dyes to monitor function• Activity propagation from DG to CA1 was

most reliable predictor of FST performance– I/O Mismatch (↓ DG but ↑ CA1 activity)

• Reversed by antidepressants• Required DG neurogenesis to reverse

• Will altering HC I/O be antidepressant?Arian et al., Science, 2007Airan et al., Science 2007

Hippocampal Input-Output Mismatch in a Depression Model

Airan et al., Science 2007

What does I/O mismatch mean?Speculation based on HC function

• Reduced input via trisynaptic path– Diminished intake of new information

• Enhanced CA1 output– Repeated replay of “old” information– Failure to update & correct errors

– HC creates cognitive maps & compares “navigation” to map; sends error signal to initiate path correction (Gagliardo et al., 2009)

What causes diminished HC inflow?New therapeutic targets?

• Disconnection from cortex– Altered entorhinal input

• Stress-induced inhibition of neurogenesis?– Not found in Airan et al.

• Stress-induced metaplasticity?– Corticosterone– NMDAR activation

Correcting the input defect? Neurogenesis & antidepressants

• Learning Psychotherapy

• Therapeutic lifestyle changes Exercise, diet, sleep, no alcohol or

drug abuse

• Environmental enrichment Stress reduction / social network

• Antidepressant medications Almost every class

• Brain stimulation methods ECT, VNS, rTMS?, DBS?

Gage, Duman, Hen, Deisseroth et al.

Why doesn’t CA1 downregulate?Stress-induced failure of homeostasis?

• Repeated stress → ↓ GABAergic steroids as brake on CA1 activity

• Chronic mild stress– ↓ 5-reductase activity → ↓ AlloP synthesis– AlloP: made in pyramidal neurons– Stress-driven autocrine/paracrine inhibitor– ↑HPA activity

Saalman et al., 2007

Why doesn’t hippocampus “overload”?

• HC = short-term, limited storage device– Why doesn’t HC reset under stress?

• How to avoid overload?– Homeostatic plasticity (adjust to load)– Homosynaptic LTD & depotentiation (same set

of synapses instruct erasure)

• What instructs hippocampus to reset?

Selective erasure of CA1 LTP by

direct entorhinal inputs

Izumi & Zorumski, J Neurosci 2008

Why is this important?• Allows cortex to erase hippocampal memories

when no longer needed

• Could this be important in depression?– Alternative way to correct HC I/O defect?– Brain stimulation methods (ECT, rTMS, DBS)?

• Sleep, synapses & depression?– Slow wave sleep: Oscillations at ~1 Hz propagate from

CTX to HC via EC (Isomura et al., Neuron 2006)– Allows synaptic resetting and self-organization

(Gilestro et al., Science 2009)

Summary

• Hippocampal dysfunction is common in psychiatric disorders– Unlikely to be the primary site of dysfunction in

many disorders

• Hippocampal involvement ensures an expanding neural network in illnesses– Plays key role in why illnesses exhibit cognitive,

emotional & motivational dysfunction