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 Challenge How 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 networks that 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. Sensory Ctx Assoc Ctx Prefrontal Ctx Parahippocampal Cortex Perirhinal Cortex Entorhinal Cortex DG CA3 CA1 Subiculum Rhinal CortexHippocampus Neocortex Hippocampal Information Flow A Primer “Where” path “What” path

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 Challenge Getting 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 – ↓ 5  -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