Water maze topics of interest to the Laboratory of Comparative Neuropsychology (LCN)
1) Multiple memory systems – This is the original research area the LCN. Brain structures
such as the hippocampus and striatum are important for different kinds of learning and
memory – cognitive vs habit formation, respectively (Petri & Mishkin, 1994). To our
surprise, we found that the hippocampus and striatum both make important contributions
to the place navigation in the water maze (Devan, Goad, & Petri, 1996) which is the gold
standard for testing cognitive memory in rodents. Our working hypothesis is that the
hippocampus is involved in the construction of cognitive maps and the medial subregion
of the striatum (corresponding to the caudate nucleus in humans) somehow allows this
cognitive information to control behavioral performance in different situations, most
notably when simple stimulus-response or other noncognitive systems are in control.

What aspects of spatial navigation performance are related to multiple memory
systems. For example, is the spatial bias rats show on the probe test comparable
to declarative memory in humans or is the persistence to search at one place
related to the strength of the previously reinforced cognitive behavior? Another is
the prolonged thigmotaxis observed in animals with damage to the medial
striatum (Devan, et al., 1996; Devan, McDonald, & White, 1999; Devan & White,
1999). Would humans with Huntington’s or Parkinson’s diseases show similar
behavior in the virtual version of the water maze? What about findings that fail to
show a dissociation between medial and lateral striatal subregions (Pistell et al.,
2009); can the water maze be used to tease such effects apart?

Given the comparative nature of the lab, we are particularly interested in studies
that directly compare rodent and human performances in the water maze. For
example, the sex difference we have observed in rodents (unpublished data),
where females perform better than males after pretraining and latent learning,
while males show more maladaptive persistent searching on the probe test,
appears consistent with hunting gathering theories of mammalian evolution and
consequently may also apply to human performance in the virtual water maze.

The effects of partial reinforcement (Devan & McDonald, 2001; Devan, Stouffer,
Petri, McDonald, & Olds, 2003), and other manipulations such as reduced
lighting and passive placement on the hidden platform (Devan, Blank, & Petri,
1992; Devan et al., 2002) are important for defining cognitive and habit
components of the water maze and may allow us to understand the complex
interactions among systems that take place during a complex behavioral
performance that involves cognitive-spatial processing.
2) cognitive enhancement - effects of drugs, nutraceuticals, food and drink (and other
endopsychopharmacological manipulations-see below).

Phosphodiesterase (PDE) inhibitors and other drugs that promote neurogenesis,
neuro- and glio-transmission, enhance information processing and increase blood
flow in addition to reducing brain inflammation to areas of the brain important
for learning and memory (Devan et al., 2005; Devan et al., 2007; Devan et al.,
2014; Devan et al., 2004). Common drink/food related chemicals such as caffeine
have recently been shown to act as PDE inhibitors. PDE10 inhibitors such as
papaverine and a novel Pfizer chemical called TP-10 are localized in striatum and
hippocampus, brain areas involved in cognition.

Melatonin and other naturally occurring chemicals [e.g., the amino acid Dserine: (Stouffer, Petri, & Devan, 2004)] that act as sleep aids may enhance
memory because long-term memory consolidation is dependent on intact
sleep/wake cycles (e.g., phase-shifting the cycle can lead to long-term impairment
in spatial memory).

Procyanidin (vitamin P) – found in high concentrations in red wine, apples and
chocolate may improve spatial memory if given for an extended period of time (410 weeks).

Effects of hormones: testosterone and estrogen have been studied a lot but others
like oxytocin, progestin and cortisol (among others) have not.

Antioxidants – fruits and vegetables that are high in antioxidants such as
blueberry, strawberry and spinach (4 a day the color way) have been shown to
improve cognition but the so-called superfruits that have recently become popular
should also be investigated. We have done preliminary work with goji and acai
juices that are 30k and 50k on the oxygen radical absorbance capacity (ORAC)
scale (by comparison blueberry, which has been shown to have enhancing effects
is 2.4k).

Omega 3 fatty acids – fish oil but also other foods. For example, one source of
fish omega 3 is sea parsley which is a culinary product but may soon be
developed as a nutraceutical supplement.

Endogenous Psychopharmacology (a.k.a. endopsychopharmacology)– is a term
we use to refer to any noninvasive manipulation which is not ingested, injected or
otherwise directly administered systemically but nevertheless has been shown to
have effects on endogenous release and levels of neurotransmitters and hormones.
Some common examples would be the release of oxytocin (important for pairbonding) by simply seeing a baby’s face, testosterone and epinephrine level
increases by watching sporting events, and stress hormone release (cortisol) when
scared or startled by something frightening.
3) Aging, neurodegenerative disease and psychological illness – Obviously a broad area of
interest that to some extent draws on the previous two basic research areas as a basis for
having translational value in a more applied research setting. Some of the potential
applied value of multiple memory systems and the use of the water maze have been
described (McDonald, Devan, & Hong, 2004; McDonald, Hong, & Devan, 2004)
although this is an open area with many research possibilities. One theory states that
there are multiple co-factors involved in age-related dementia (McDonald, 2002),
therefore instead of looking for a silver bullet of aging or a single therapeutic treatment,
complex combinations of compounds may target interactive signal transduction
pathways in the brain (Pistell et al., 2007).

Therapeutics and nutraceuticals to treat Alzheimer’s, Parkinson’s and
Huntington’s diseases, among others are of particular interest and immense
importance as technological advances increase the average lifespan of individuals
in developed nations increases.

Studies with aged animals are expensive but there are drugs that mimic certain
aspects of aging, for example cholinergic blockade with scopolamine (Devan, et
al., 2004; Janas et al., 2005). In instances where we have data with aged animals
the preliminary results show that PDE5 inhibitors may have some beneficial
effects in the water maze, but by no means is it a cure for age-related dementia.

We believe that adaptations of the water maze may be ideal for developing animal
models of anxiety, schizophrenia and obsessive compulsive disorders.
Unpublished data from our lab has revealed a curious behavior when rats are
passively placed on the platform for a latent learning exposure. Often the rats will
leave the safety of the platform to go and check other hidden locations where they
have previously escaped. The anxiety of being left on the platform for an
extended period leads to a checking behavior that is in some ways similar to
checking behavior in OCD patients. Drug induced schizophrenic symptoms may
also be investigated using a similar behavioral test that we have termed spatial
response initiation.
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