Where comparative psychology meets clinical psychology: Examining sex differences in psychiatric disorders from a rat’s perspective

This semester I have the privilege of teaching three sections of introductory psychology. While teaching this many sections generally makes things challenging (the third time being the charm does not apply since by then you can’t keep straight what you have or have not covered), doing so with online, virtual classes that seem never to end, is particularly trying. An experience where some thrive and some survive!

Despite these challenges, my first week of classes was successful. In one short class (three times!), the students learned there was more to psychology than psychopaths, therapy, and criminal profiling. Although some students, especially those who had previously taken a high school psychology class, mention cognitive psychology or social psychology, almost none had heard of comparative psychology.

Going to the dogs, and flies, and rats

Not unexpectedly, many students are familiar with animal research within the context of pharmaceuticals or cosmetics. However, most have not been exposed to animal models representing various psychiatric or psychological disorders. My favorite early examples to use in class are narcoleptic flies or dogs – students are surprised every time.

The intersection of clinical psychology and comparative psychology has been around since the early days of psychology. Still, it seems to have to be rediscovered every decade or so (see a somewhat recent essay on this topic). Various pamphlets published by the American Psychological Association report that about 7-8% of psychological laboratories used animals in research to investigate different topics within clinical psychology and psychoactive drugs and environmental toxins. Unfortunately, these aspects of psychology are not well known by the general public, much less first-year college students.

Following a quick overview of the field of psychology and my own personal preference for studying cognition and behavioral development in marine mammals, my students are able to quickly demonstrate their facility with the breadth of psychology. Despite their newly minted knowledge of comparative psychology, only a handful will mention comparative psychology in their first reflection on the field of psychology. In their minds, how could a rat’s performance on different behavioral tests provide information about the underlying vulnerabilities and sex differences of various psychiatric disorders, especially ADHD, schizophrenia, major depression, or anxiety?

Are Male Rats from Mars, and Female Rats from Venus? (to borrow from the 1992 best-selling self-help book title)

Tara Chowdhury, Kathryn Wallin-Miller, Alice Rear, Junchol Park, Vanessa Diaz, Nicholas Simon, and Bita Moghaddam, collaborated on a series of studies in which they investigated sex differences in rat performance on a series of behavioral tests. They posited that the variations in sex prevalence for specific psychiatric disorders might reflect biological differences in pathophysiology. Specifically, the authors focused on reward-seeking and punishment-avoidance behaviors, which may be key components of motivation in disorders like ADHD, schizophrenia, anxiety, and major depression.

Published in Psychonomic Society’s journal Cognitive, Affective, & Behavioral Neuroscience, Chowdhury and her colleagues argued that female rat performance on some behavioral tests may provide insight into why women tend to experience major depression or anxiety more than men. Likewise, they also suggested that male rat performance on the same tests may identify why men tend to experience schizophrenia and ADHD more frequently.

To test their hypothesis, the researchers conducted three tasks with Long-Evans rats or Sprague-Dawley rats: (1) a Punishment Risk Task (PRT), (2) an Approach Avoid Task (AAT), and (3) cognitive flexibility tasks. All tests involved an experimental chamber that required some action (lever press or nose poke) to receive a sugar pellet. Shock was used in the PRT and the AAT, but not in the cognitive flexibility tasks. As the schematic from another study illustrates below, the nose poke ports were positioned opposite of the food trough (the lever was also opposite of the food trough in the study examined for this article, unlike the schematic). A light or tone was used to signal the rats when the reward would be available if the correct action was performed (lever press or nose poke).

Image from Yuki, S., & Okanoya, K. (2017). Rats show adaptive choice in a metacognitive task with high uncertainty. Journal of Experimental Psychology: Animal Learning and Cognition, 43(1), 109–118. https://doi.org/10.1037/xan0000130

Shocking but sweet: Punishment Risk Task

The PRT task was used to assess the rats’ responses to unpredictable shocks and the perception of potential threats, which acts as a proxy for human anxiety. Basically, rats learn to poke their noses into a port on one side to receive a single sugar pellet in a trough on the other side of the chamber. Once the rats have learned this action, they then progress through 3 blocks in which no shock, 6% probability of a shock, or 10% probability of shock, respectively per block, is experienced following the nose poke action (see panel a in the figure below). This increasing, but varying, probability of receiving a shock induces anxiety-related behaviors.

For this task, female rats were slower to respond to the light cue as the probability of shock increased, while the male rats showed no difference in latency across the three blocks (see panel b in the figure above). However, there was no sex difference in the time it took to retrieve the reward. The authors concluded that while both females and males were equally motivated to retrieve the food (sugar rules!), the female rats were more affected by the possibility of the punishing shock than the male rats and were therefore slower to respond (shock schools – female rats anyway).

Life’s Conundrum-Sugar or Spice: Approach Avoid Task

The AAT task was a concurrent task, which required the rats to choose between one of two signaled consequences:

  1. approach (signaled by light), in which an action (e.g., nose poke) was rewarded with a sugar pellet, or
  2. avoid (signaled by tone), in which the other action (e.g., lever press) prevented the onset of a foot shock

For humans, this rat behavioral task simulates optimal strategies in making choices between rewards and punishments within specific contexts (a balancing act of desire and survival). These kinds of choices are played out in psychiatric disorders, such as anxiety, substance abuse, and major depression. In the case of rats (and probably humans), shocks are anxiety-provoking, but sugar pellets are tasty. So, which outcome am I willing to endure when both options are available and one is signaled? To test this context, all rats first had to receive training for each consequence separately before they were tested with both options. The figure below illustrates the protocol used for this task (see panel a in the figure below).

When given trained on each context, female and male rats learned both the reward cue (panel b above) and avoidance cue (see panel c in the figure above) at similar rates. One exception was noted, female rats learned the initial avoidance behavior in fewer sessions than the male rats when hand-shaping was used, suggesting that the females may have been more sensitive or reactive to the avoidance context. However, during the full approach avoid task when both options were available, no sex differences were found for the number of trials needed to reach criterion, but males did successfully avoid shocks more frequently than females. Interestingly, some females were avoiders (avoided shock entirely) and others were escapers (escaped once the shock had begun), which may have implications for how individual differences may play a role in anxiety acquisition and treatments.

Walking the Tightrope

To expand on the influence of anxiety in this task, the authors conducted two other tests in which they

  1. tested the rats’ responses to the AAT while under the effects of an anxiety-inducing drug (FG7142), and
  2. compared the performance of rats that had been trained on the AAT to rats that had not been trained on an elevated plus maze.

As the different doses of drug increased anxiety, both male and female rats decreased their approach behavior and increased the latency to respond to the reward cue. The rats were still motivated to eat the sugar pellet though (clearly a valuable reinforcer). However, at the highest level of the anxiety drug, male rats were slower to respond to the cue to avoid the shock, despite being faster than the female rats at the other dose levels. The elevated plus maze resulted in female rats with AAT training were more likely to stay in the closed arms than the male rats with AAT training while the AAT-naïve rats showed equal time in closed and open arms. These results suggested that anxiety-driven avoidant behavior in female rats may be related to accumulated aversive experiences, rather than a biologically driven predisposition. However, additional work is needed to better understand this distinction.

Cognitive Overload?

Results from cognitive flexibility tasks, which included discrimination learning, reversal learning, set shifts indicated that male and female rats did not respond any differently across the various tasks. In fact, cognitive overload did not degrade performance differentially. Ultimately, this study of rat behavior under certain reward and punishment conditions culminated in the conclusion that when the task required purely reward-motivated actions, no matter the cognitive load, male and female rats learn and respond similarly. The promise of sugar is universally effective!

However, when the threat of punishment was introduced, females became more hesitant to respond in the risky contexts. These results parallel human responses: females display increased vulnerability to anxiety when the risk of punishment is present while males exhibit reduced responsiveness to the risk of punishment, which may heighten impulsivity, as seen in drug abuse or ADHD cases.

Synergy Unite

As illustrated by this study, comparative psychology and clinical psychology can complement each other. Although rodent models may seem simple in nature, understanding the influence of history with aversive and rewarding experiences may be the key to solving the current mysteries of human psychological disorders and treatments. In the meantime, research, such as conducted by Chowdhury and her colleagues, will provide excellent reading material for my general psychology, learning, and comparative psychology students that will hopefully spark their interest in other aspects of psychology.

Psychonomics article focused on in this post

Chowdhury, T. G., Wallin-Miller, K. G., Rear, A. A., Park, J., Diaz, V., Simon, N. W., & Moghaddam, B. (2019). Sex differences in reward-and punishment-guided actions. Cognitive, Affective, & Behavioral Neuroscience, 19(6), 1404-1417. https://doi.org/10.3758/s13415-019-00736-w

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