The assessment of working memory in rodents

1. The assessment of working memory in rodents Dr. Paul Dudchenko University of Stirling United Kingdom

2. outline • how is working memory defined? • how is working memory measured in the rodent? • neural substrates of working memory

3. How is working memory defined? Baddeley and Hitch (1974): Working memory is comprised of a visual-spatial sketchpad, an episodic buffer, a phonological loop, all of which are controlled by a central executive. (humans) Honig (1978): Working memory is a representation of a cue over a delay period in which the cue is not present, to be subsequently used to respond. (pigeons) Olton, Becker, and Handelman (1979): Spatial working memory, but not reference memory, depends on the hippocampus. (rats) Goldman-Rakic (1980s; Fuster, Kubota 1970s): Working memory operationalised as the on-line representation of a stimulus over a delay period in the pre-frontal cortex. (monkeys) Dudchenko (2004): Working memory is a short term memory for an object, stimulus, or location that is used within a testing session, but not typically between sessions. (rats)

4. Working memory may underlie ability to imagine future events. Neanderthals had a limited capacity to hold and manipulate information. “On the basis of brain-imaging studies and other research, [Daniel] Schacter and Donna Rose Addis of the University of Aukland have concluded that the same neural networks Are implicated in both remembering the past and imagining the future and that both processes probably involve something like Baddeley’s proposed episodic buffer. “Working memory is criticially important for constructing simulations of future events,” Shacter says.” Michael Balter (2010) Did working memory spark creative culture? Science

5. outline • what is working memory? • how is working memory measured in the rodent? • neural substrates of working memory

6. all spatial working memory tasks • all depend on the hippocampus/medial temporal cortex From: Hagan and Jones (2005) Predicting drug efficacy for cognitive deficits in schizophrenia Schizophrenia Bulletin, 31(4): 830-853

7. How long after the determining stimulus can an animal wait and still react correctly? (pg. 2) 1913

8. Hunter observed delay-dependent memory. Rats could remember which light had been illuminated after a delay of up to 10s. Hunter (1913) However: “The rat, when put into the release box during the delayed reaction, oriented immediately to the light with its entire body, and began a series of attacks on that side of the box in an effort to get out.” (pg. 41)

9. “Mediating behaviours” during the delay between the to-be-remembered stimulus and the response has also been observed in operant delayed non-matching to position tasks (Dudchenko & Sarter (1992); Chudasama & Muir (1997)). sample delay choice • So, one of the intrinsic challenges in developing valid rodent • memory tasks is ensuring that delays can’t be bridged by a • behavioral response.

10. A simple way of testing short-term memory is the delayed alternation task on a T-maze. delay sample choice Start arm Start arm

12. Performance on the T-maze is delay-dependent number of correct responses chance memory delay

13. 4 3 Average number correct chance 2 1 5 min 20 min 60 min 120 min 240 min Memory delay Working memory on the radial arm maze Olton and Samuelson (1976) Bolhuis et al (1996) From: Neuroscience exploring the brain, Bear, Connors, Pardiso (2001)

14. outline • what is working memory? • how is working memory measured in the rodent? • neural substrates of working memory

15. Brain circuits implicated in neurocognitive deficits in schizophrenia Prefrontal Cortex Amygdala Striatum VP Temporal Cortex BFCS Midbrain DA neurons Raphe 5HT neurons slide from Dr. Holly Moore

16. 18 14 Number correct 10 chance 6 2 hippocampus lesion control 1 2 3 4 Session block percent correct chance memory delay Aggleton et al. (1995) J. Neuroscience

17. A spatial span memory task

21. Odor span memory in rodents is excellent, but may not require the hippocampus. • The hippocampus is required for remembering the order in which odors are presented • (Fortin et al. 2002). • Humans with hippocampus damage are impaired on an odor span task (Levy et al. • 2006).

22. Odor span: neural substrates • Removal of basal forebrain cholinergic neurons impairs performance on this task (Turchi • and Sarter, 2000). • Removal of cholinergic inputs to the entorhinal cortex does not impair memory for familiar • odors, but does impair memory for new ones (McGaughy et al. , 2005). • Mice without α7 nicotinic acetylcholine receptor are impaired on the odor span task • (Young et al. 2007). • Nicotine improves odor span memory; scopolamine and mecamylamine impair it • (Young et al. 2006; Rushforth et al. , 2010). • Odor span also impaired in mice that over-express β-amyloid (Young et al. 2009).

23. Neurons in the hippocampus fire with respect to the rat’s future destination. no reward reward no reward reward Ainge et al. (2007) Journal of Neuroscience

24. goal 2 goal 3 goal 4 goal 1

25. if food is found on every maze arm (so no memory is required)… food food food food …place cells no longer encode different maze arms Stevenson et al. (2010) SFN abstracts

26. summary • notions of working memory have developed independently • in the human and non-human literatures • in rodents, working memory has been operationalized a • delay-dependent, short-term memory for a location, object, • or stimulus • in rodents, spatial working memory requires the temporal • cortex and hippocampus, and neurons in the hippocampus fire • with respect to future goal locations • as such, rodent spatial working memory tasks may reflect • the “episodic buffer” portion of Baddeley’s human working memory • model

28. Differential activity was also seen before the second choice point

29. Delay box food food B) A) first run start box goal box second run Dennis (1939) Ladieu (1944)

30. Cue 6 No cue 5 Average Number Correct 4 chance 3 2 0 s 10 s 1 min 2 min 5 min 10 min Memory Delay

32. sample choice Ennaceur & Delacour (1988)

33. sample delay (0-6 sec) choice

34. Control Hippocampus lesion

35. An olfactory “span” memory task

36. All animals chance Distribution of correct choices on the odor span task with 12 odors 100 80 60 % correct 40 20 0 0 1 2 3 4 5 6 7 8 9 10 11 number of odors to remember (span)

37. left-turn trials right-turn trials * * *

38. left-turn trial right turn trial Modified T-maze spatial alternation task Do place cells that fire on the central stem of the T-maze differentiate between left-turn and right-turn trials? Wood, Dudchenko, Robitsek, Eichenbaum (2000) Neuron, 27: 623-633