The amount of preclinical data being presented at the BAP Summer Meeting has been dwindling over the years, in favour of clinical and non-clinical human research. This post-doctoral symposium was put together by myself and Dr Claire Hales from the University of Bristol to showcase preclinical work and to highlight the importance of using translational animal models and behavioural measures in psychopharmacology.
First up was Dr Anna Huber from Oxford University and her talk titled: “Mind your cues! – How the COMT-Met mouse model helps us understand the connections between cortical dopamine, cue salience and reinforcement learning.”
Dr Huber began her talk by describing how the ability to associate a cue with either a positive or negative outcome is a valuable adaptive process in both humans and animals, and stressed that, while we know a lot about how reward affects this learning process, we are less clear on how the salience of the cue is involved. The transgenic mouse model employed in Dr Huber’s studies mimics a polymorphism found in the human catechol-O-methyltransferase gene (COMT Val158Met). COMT plays an important role in regulating dopamine levels in the frontal cortex, and its activity is reduced in Met-allele carriers, therefore the model is a particularly useful tool for understanding the role of cortical and striatal dopamine in associative learning.
Dr Huber’s initial studies aimed to assess the effect of the COMT genotype on a Pavlovian discrimination conditioning paradigm that used two cue types – white noise (WN), or an auditory tone (T). Whilst initially there appeared to be no overall effect of genotype on learning of the conditioned stimulus, when the data was split according to the identity of the CS+ (either WN or T), the transgenic animals were shown to outperform wild types when the WN cue was the CS+, but underperform when the CS+ was the T cue. It was then shown that by boosting the salience of the T cue (by increasing its volume), the performance of the transgenic animals was increased to match that of the wild types. Using fast-scan cyclic voltammetry, Dr Huber showed that more dopamine was released in the nucleus accumbens (NAc) in response to the initial presentation of the WN cue than in response to the T cue, suggesting that prior to learning the cue-reward association, dopamine release represents a neural substrate of cue salience. She also showed that the effect of COMT genotype on NAc dopamine release was specific to the cue presentation, not the reward outcome.
Taken together, these data suggest that cortical-striatal dopamine circuitry mediates salience effects in associative learning, and Dr Huber concluded her talk by stressing that careful selection of the cue type is critical in conditioning tasks, and that dopamine release does not necessarily mirror the animals’ performance.
Next to speak was Dr Andrew Hayward, currently working at Aalborg University in Denmark, but presenting work that he had undertaken during his time at the University of Manchester, titled “Low attentive and high impulsive rats: a translational animal model of ADHD and disorders of attention and impulse control.”
Dr Hayward’s work focused on improving the translational value of rodent tasks through behaviour-based modelling, and he began his talk by emphasising failures of clinical trials due to a lack of translation in clinical tasks of attention. Animal models with enhanced construct validity and translation to the clinic are therefore essential to improve our understanding of the underlying pathophysiology of ADHD and to develop improved treatments.
It is thought that the symptoms of low attention and high impulsivity in ADHD represent the extremes on a continuum of behaviour present within the general population, and the theory of optimal arousal suggests that, depending where an individual lies on an inverted-U relationship between arousal and performance, this will determine how they will respond to treatment. In the 5 choice serial reaction time task (5C-SRTT), a behavioural paradigm used to assess visuo-spatial attention and impulsivity in rodents (translating to the continuous performance task used in the clinic), the animals also show a continuum of performance. Therefore, separating the animals based on extreme behavioural traits provides an unbiased method of modelling that may provide better translational validity.
Dr Hayward proceeded to demonstrate the importance of behavioural grouping by providing data on the effects of several drugs in the 5C-SRTT. Methylphenidate was shown to improve performance in low attentive animals, but impair performance in high attentive animals, an effect that would have been missed if the animal population was assessed as a whole. Similarly encenicline, a partial nACHR α7 agonist, improved attention, vigilance and impulsive action in low attentive animals only, which makes it a particularly interesting drug for clinical use.
Overall it is clear from Dr Hayward’s presentation that these treatments act differently in animals with different behavioural traits, therefore behavioural grouping represents an important tool with face, construct and pharmacological validity. Since the model is not limited to a particular underlying mechanism, it also offers the flexibility to study other conditions characterised by low attention and high impulsivity, such as schizophrenia, Parkinson’s disease and obsessive compulsive disorder.
Our next speaker was Dr Emma Cahill from the University of Cambridge and her talk titled: “Development of a hypervigilance model using rodent 22-khz ultrasonic vocalisations.”
The heterogenous nature of psychiatric disorders such as anxiety, makes it extremely challenging to model them in animals, however targeting a specific symptom perhaps offers an easier avenue of investigation. Dr Cahill’s work focuses on ‘hypervigilance’, a state of heightened sensory sensitivity that manifests as an exaggerated response to an external stimulus. To do this she is analysing the 22-kHz ultrasonic vocalisations (USVs) that are emitted as alarm calls in rats, as a potential behavioural indicator of anxiety, as well as their relationship to fear-induced freezing behaviour.
In a fear conditioning procedure where rats learned that an auditory tone (CS) predicted an unavoidable footshock (US), Dr Cahill found that rats emitted USVs during the preCS period, whilst presentation of the CS suppressed USVs and induced freezing behaviour. She suggested that this change in behaviour reflects a switch between the animals’ state of vigilance and anxiety in anticipation of danger, and their acute fear of the CS. These data present the exciting possibility that rats are indeed capable of ‘self-reporting’ a negative mood state. Dr Cahill then designed a modified task in which the salience of the CS presented during the test phase was reduced (by reducing its volume), in order to screen for hypervigilance. She found that only rats presented with the CS at the same volume as during conditioning emitted USVs, and that the more elusive CS reduced freezing behaviour, indicating that the animals were sensitive to a change in cue salience. Furthermore, freezing behaviour was increased in rats that vocalised, compared to those that didn’t.
Whilst the timing of USVs in these animals may reflect a change in state anxiety during the behavioural task, the fact that only 30% of rats emit these alarm calls indicates that differences in trait anxiety also exist. An interesting question raised during the post-presentation discussion asked whether it would be possible to predict which animals would vocalise during the behavioural task.
Last to speak in this symposium was Dr Phil Gaskin, also from the University of Cambridge on his research in “Anxiety and anhedonia: overactivity in the marmoset subgenual anterior cingulate”.
Dr Gaskin works with the common marmoset: a species that, much like humans, displays complex social and emotional behaviours. Together with the structural similarities between the marmoset and human cortical regions, these animals provide a good model for studying the role of the anterior cingulate cortices in the regulation of emotion. The presentation began with Dr Gaskin highlighting the sheer importance of depression research and emphasising how little we currently know about the disorder. He described how neuroimaging data has revealed elevated activity in the subgenual cingulate cortex (sgACC/25) associated with clinical depression and negative affective biases.
In order to investigate this region of interest, Dr Gaskin employs the use of a variety of behavioural tasks that tap into different aspects of anxiety and anhedonia and relates these behaviours to an autonomic cardiovascular profile obtained via surgically implanted radiotelemetry devices. Of particular note is the use of a human-intruder paradigm, in which the animals are confronted with an unfamiliar human intruder (an experimenter wearing a rubber Halloween mask) in the home-cage environment. This elicits a distinct set of uncertainty-induced anxiety behaviours from the marmosets (and several murmurs of amusement from the audience!). Using these methods Dr Gaskin has examined the effects of overactivation of sgACC using an infusion of a glutamate transporter inhibitor. He found that this overactivation reduced anticipatory appetitive arousal and induced motivational anhedonia in a progressive ratio task of operant responding, without impacting on consummatory arousal or reward consumption. In contrast to this profile of reduced reward sensitivity, the behavioural and cardiovascular responses to uncertainty-induced anxiety in the human-intruder test were exaggerated, and habituation to the aversive stimuli was impaired.
The test battery used by Dr Gaskin has clearly provided a wealth of information regarding the effects of overactivation of sgAcc/25, and has served to unpick the many aspects of reward processing relevant to anxiety and depression. His ongoing work assessing the effects of both conventional and novel antidepressant drugs on these behaviours is crucial in determining the underlying neurobiological mechanisms in depression and its treatment.