Neuroscience. 2015 Sep 10;303:364-77. doi: 10.1016/j.neuroscience.2015.07.003.

Altered visual processing in a rodent model of Attention-Deficit Hyperactivity Disorder.

Brace LR1, Kraev I1, Rostron CL1, Stewart MG1, Overton PG2, Dommett EJ3.
  • 1Department of Life, Health and Chemical Sciences, The Open University, Milton Keynes MK7 6AA, UK.
  • 2Department of Psychology, University of Sheffield, Western Bank, Sheffield S10 2TN, UK.
  • 3Department of Psychology, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 8AF, UK. Electronic address: Eleanor.dommett@kcl.ac.uk.

 

Abstract

A central component of Attention-Deficit Hyperactivity Disorder (ADHD) is increased distractibility, which is linked to the superior colliculus (SC) in a range of species, including humans. Furthermore, there is now mounting evidence of altered collicular functioning in ADHD and it is proposed that a hyper-responsive SC could mediate the main symptoms of ADHD, including distractibility. In the present study we have provided a systematic characterization of the SC in the most commonly used and well-validated animal model of ADHD, the spontaneously hypertensive rat (SHR). We examined collicular-dependent orienting behavior, local field potential (LFP) and multiunit responses to visual stimuli in the anesthetized rat and morphological measures in the SHR in comparison to the Wistar Kyoto (WKY) and Wistar (WIS). We found that SHRs remain responsive to a repeated visual stimulus for more presentations than control strains and have a longer response duration. In addition, LFP and multiunit activity within the visually responsive superficial layers of the SC showed the SHR to have a hyper-responsive SC relative to control strains, which could not be explained by altered functioning of the retinocollicular pathway. Finally, examination of collicular volume, neuron and glia densities and glia:neuron ratio revealed that the SHR had a reduced ratio relative to the WKY which could explain the increased responsiveness. In conclusion, this study demonstrates strain-specific changes in the functioning and structure of the SC in the SHR, providing convergent evidence that the SC might be dysfunctional in ADHD.

KEYWORDS: distractibility; orienting; spontaneously hypertensive rat; superior colliculus

PMID: 26166731

 

Supplementary text

Attention Deficit Hyperactivity Disorder (ADHD) affects a significant proportion of individuals as the most common neurodevelopmental condition and diagnosis occurs both in children and adults (Biederman & Faraone, 2005). It is reasonably well treated with stimulant and non-stimulant treatments but the neurobiological basis of the condition is not well understood (Biederman, 2005). Much research to date has focussed on the dopaminergic and, to a lesser extent, the noradrenergic systems. However, in this study, rather than look at the condition as a whole and focus on the neurotransmitters systems involved, we opted to investigate one particular symptom of the condition – in this case distractibility. Enhanced distractibility is one of the most common features of ADHD (Barkley & Ullman, 1975) and therefore elucidating its biological basis may offer substantial insight into the condition.

We presented key existing evidence that the superior colliculus is a neural correlate of distractibility; notably that it is critical for responses to novel and/or salient stimuli and that it plays a central role in eye movements. Furthermore, lesion studies have found that increased activity in the colliculus is associated with heightened distractibility. Previously, Prof Paul Overton (Sheffield University, UK) proposed that ADHD, or more specifically the heightened distractibility in ADHD, may arise from an over-active superior colliculus (Overton, 2008). This was supported with our previous work showing altered air righting behaviour in the Spontaneously Hypertensive Rat (SHR) model of ADHD (Dommett & Rostron, 2011). However, whilst air-righting is collicular-dependent, it is not a marker of distractibility. In addition, the previous study, only examined behaviour and did not record collicular activity or examine morphological features. To address this gap in the research we conducted the present study, hypothesizing that there would be a significant difference in visual responsiveness, collicular activity and morphological features in the SHR compared to two control rat strains (the Wistar Kyoto and the Wistar) (Brace et al., 2015a).

The behavioural data was collected using a simple laboratory set-up, effectively an empty water maze with a visual distractor stimulus (green LED) placed in the middle of the maze. After habituation to the test arena, the rats’ responses to 10 consecutive light flashes (inter-stimulus interval 5 mins) were measured. This set up is shown in Figure 1.

 

 

Figure 1

Figure 1: Examples of an animal’s behaviour within the arena. A: the animal is orientating away from the stimulus (deemed as no response to the stimulus). B: the animal is interacting with the stimulus (deemed as responding to the stimulus).

 

Note that the data was collected in the active phase of the test animals and under red lighting, with a white noise generator. The experimenter controlled the paradigm from outside of the room. This test can be used as a crude measure of distractibility (Clements, Devonshire, Reynolds, & Overton, 2014; Robinson & Bucci, 2014) and offers a distinct advantage over more complex tests because it does not require food or water reinforcement. This is important in studies employing the SHR because they been found to have consistently lower body weight and drink different amounts of fluid at baseline, making such reinforcers potential confounding variables in strain comparisons (Dommett & Rostron, 2013). The behavioural data showed that the three strains of rat had similar responses qualitatively and in terms of response duration but the SHR failed to habituate to the stimulus with almost 70% responding to the stimulus on the final presentation, in contrast to the 11% for the two control strains.

After behavioural testing, we also collected electrophysiological data in a number of animals, measuring both local field potential activity and multiunit data in the superior colliculus under urethane-anaesthesia. The superior colliculus is made up of seven layers, the top three of which are dedicated to visual processing, and referred to as the superficial layers whilst the deeper layers respond to a wider variety of stimuli and demonstrate multimodal integration (Figure 2).  Given our focus on visual responsiveness all recordings were made in the superficial layers.

 

 

Figure 2-2Figure 2: A coronal section through the rat brain of the superior colliculus at -6.3 mm from Bregma. The three superficial layers; and the four deeper layers; Zo: zonal layer; SuG: Superficial grey; Op: Opticum; InG: Intermediate grey; InWh: Intermediate white; DpG: Deep grey; DpWh: Deep white; PAG: Periaqueductal grey; Aq: cerebral aqueduct (Adapted from Paxinos and Watson, 1998).

 

The superficial layers are very easy to locate for recordings because they show a clear light response to a whole-field light flash once the animal has been dark adapted. An example of this response is shown on a raw trace in Figure 3, with the arrows indicating the time of the light flash.

 

 

Figure 3Figure 3: An example raw trace taken from the superficial layers of the superior colliculus showing the visual light response to repeated light stimulus (occurring at the time points shown by the arrows).

 

These data showed that the SHR were more likely to produce multiunit but not local field potential responses. Multiunit responses can be considered as the output of the structure because the recorded data is a collection of action potentials or spikes. By contrast the local field potentials are believed to represent the post-synaptic activity within a structure. The results found, therefore, suggest that the superior colliculus is receiving similar incoming information in all three strains of rat, hence there being no differences in the local field potential data. However, it seems that the colliculus responds differently in the different strains with the SHR having amplified responses. This is in line with the hypothesis by Overton (2008) that increased distractibility may result from a hyperactive colliculus.

The final stage of our study was to exam morphological characteristics of the colliculus in the three strains, again focussing on the superficial layers of the colliculus. This part of the study demonstrated no significant differences in volume, neuron and glia number and density. However, there was a significant change in the glia:neuron ratio with a lower ratio in the SHR, indicating fewer glia for the number of neurons present. Given the glial cells measured were highly likely to be astrocytes, this can be considered support for previous work indicating that there is a problem with astrocytes in ADHD (Killeen, 2013; Todd & Botteron, 2001).

Following on from this study, we have since investigated auditory processing using the same experimental paradigms, focussing this time on the intermediate and deep layers of the colliculus (Brace et al., 2015b). This was conducted because, as stated above, the colliculus is a multi-modal structure and, therefore, it might be expected that similar findings will occur with different stimulus modalities. We found no evidence of increased distractibility in the behavioural data for auditory stimuli despite evidence from people with ADHD indicate auditory processing impairments exist (Claesdotter-Hybbinette, Safdarzadeh-Haghighi, Rastam, & Lindvall, 2015; Gomes et al., 2012; Moreno-Garcia, Delgado-Pardo, & Roldan-Blasco, 2015). However, we suggest that this may have arisen due to cochlear hearing loss in the SHR i.e. a modality -specific impairment (Li, Gong, Yang, & Yu, 2003; McCormick, Harris, Hartley, & Lassiter, 1982; Rarey, Bicknell, & Davis, 1986; Tachibana et al., 1984). Furthermore, the electrophysiology data indicate that the colliculus in the SHR may still be hyper-responsive, normalising the amplitude of auditory responses that would otherwise be reduced due to the hearing impairment. The morphological measures of collicular volume, cell density and ratios did not indicate this potential hyper-responsiveness had a basis at the structural level examined. These findings have implications for future use of the SHR in auditory processing studies and may represent a limitation to the validity of this animal model.

 

Ellie Dommett ProfleContact

Dr Ellie Dommett

Institute of Psychiatry, Psychology and Neuroscience (IoPPN),

Second Floor, Addison House,

King’s College London,

London. SE1. 1UL.

Eleanor.dommett@kcl.ac.uk

 

 

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