How a Cellular Neuroscientist Thinks About Psychiatric Disorders

1. How a Cellular Neuroscientist Thinks About Psychiatric Disorders June 2011

2. What is this?

3. A Hippocampal Microculture GFAP (astrocytes) MAP2 (dendrites) VGLUT1 (vesicles)

4. A Major ChallengeHow do we get from here to there?

5. What is psychiatry? • Psychiatry is a medical specialty concerned with disturbances of the human mind and behavior

6. But…what is the “mind”? • Mind = the result of processing in parallel but integrated brain networksthat allow humans to do three major things: • Think (attention & working memory) • Attach value to things (emotions) • Set & pursue goals (motivation) LeDoux, Synaptic Self LeDoux et al.

7. 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

8. Example: 3 Stages of Addiction Koob & Volkow, 2010

9. What happens to brain networks in psychiatric disorders? Lessons from the hippocampus

10. 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”)

11. 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

12. Hippocampal Information Flow A Primer DG Sensory Ctx Assoc Ctx Prefrontal Ctx “Where” path CA3 Parahippocampal Cortex Entorhinal Cortex Perirhinal Cortex CA1 “What” path Subiculum Rhinal Cortex Hippocampus Neocortex

13. 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

14. How does the hippocampus learn? Long-term synaptic plasticity Hippocampal Slice Long-term potentiation (LTP) Physiology Recording Rig

15. A Major ChallengeGetting from here to there?

16. 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, 2007 Airan et al., Science 2007

17. Hippocampal Input-Output Mismatch in a Depression Model Airan et al., Science 2007

18. 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)

19. 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

20. 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.

21. Why doesn’t CA1 downregulate?Stress-induced failure of homeostasis? • Repeated stress → ↓ GABAergic steroids as brake on CA1 activity • Chronic mild stress • ↓ 5a-reductase activity → ↓ AlloP synthesis • AlloP: made in pyramidal neurons • Stress-driven autocrine/paracrine inhibitor • ↑HPA activity Saalman et al., 2007

22. 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?

23. Selective erasure of CA1 LTP by direct entorhinal inputs Izumi & Zorumski, J Neurosci 2008

24. 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)

25. 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