Figure 1: Parvalbumin interneurons are also
categorized as "basket" cells because of their shape and they fire with a high frequency. Cartoon by Dr. Immy Smith, @Cartoon_Neuron |
Parvalbumin interneurons are a type of cell that is
important for learning and memory. In people with schizophrenia, the number of
parvalbumin interneurons is reduced. People with schizophrenia also tend to
have deficits in working memory and task shifting, a type of cognitive
flexibility. Sam hypothesized that cognitive flexibility is related to a
decrease in parvalbumin interneuron number.
To test this hypothesis he used mice with a gene,
Ccnd2, deleted. Mice with missing or altered genes are called transgenic mice
and, in this case, they're named Ccnd2 knock-out mice (Ccnd2-KO). Deleting the
Ccnd2 gene results in mice with 40% fewer parvalbumin interneurons in
adulthood. In order to assess cognitive flexibility he used a strategy
switching cross maze, which is a rodent equivalent to the Wisconsin Card Sorting Test used in humans.
Figure 2: The egocentric rule. |
The two rules used in the task are egocentric (ego =
self, centric = centered) and allocentric (allo = other). For an egocentric
rule, the mouse is trained to always "turn right", for example
(Figure 2). So no matter if the mouse is placed in the west or east side of the
maze, they are rewarded to always turn right.
An example of the allocentric rule,
is when mice are trained to always "go north" (Figure 3). When the
mouse is placed in the west arm of the maze it is rewarded to turn north, which
is its left. When placed in the east arm of the maze it is rewarded to turn
north, which is now its right.
Figure 3: The allocentric rule. |
Some mice learned the egocentric version first and some
learned the allocentric version first. When the rule was switched, there were
two types of errors that could be made. If the mouse continued to turn the same
way they were trained rather than the new way it was a "perseverative
error", because they persevered in trying to solve the maze the old way. People
with schizophrenia tend to make preservative errors when learning a new rule in
the WCST. In the strategy switching maze, if mouse turned in a new direction that
they had never been rewarded for, it was a "never reinforced" error.
Sam trained the mice for 24 trials/
day until they chose the correct arm 8 out of 10 times (80% efficiency). During
initial learning, the number of errors made by non-transgenic and Ccnd2-KO mice
was not different. When the rule was switched, Ccnd2-KO mice had difficulty
learning the new rule. They made more errors than the non-transgenic mice,
especially if they had first learned the allocentric rule. The type of error
was surprising. Rather than making “perseverative” errors, as people with
schizophrenia tend to do in the WCST, the mice made more "never
reinforced" errors. It seemed they weren't learning the new rule effectively
but it wasn’t because they were still stuck on the old rule.
The non-transgenic animals were particularly good at
switching to the new rule if they learned the egocentric version first. Sam
thinks this is because while they were learning the egocentric version they
passively made a spatial map of the maze even though they didn't need to in
order to solve the maze. This type of learning is called latent learning. It
seems to have given the non-transgenic mice an advantage when learning the
allocentric version of the task second.
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