whjnorton

habenula 2

Image taken from http://journal.frontiersin.org/article/10.3389/fnins.2011.00138/full

Although the zebrafish has already been established as a model organism to investigate the genetic and neurological basis of aggression the circuits in the brain that control this behaviour are still not well understood. One area of the brain that has been intensively studied is the dorsal habenula, which shows a striking asymmetry in organisation, gene expression and connectivity between the left- and right halves of the brain. The habenula is also located superficially in the zebrafish brain (making it easy to access) and also controls lateralised behaviours. For example, adult zebrafish prefer use the right eye to examine novel objects whereas the left eye is used to look at familiar objects (Barth et al., 2005). Furthermore, disrupting habenula symmetry makes adult zebrafish more anxious (Facchin et al., 2015).
The habenula has already been implicated in fear conditioning as part of a circuit that send projections to the interpeduncular nucleus (IPN) and the dorsal tegmental area (equivalent to the periaqueductal grey matter in mammals) via the raphe nucleus, the most prominent source of 5-HT in the vertebrate brain (Chou et al., 2016).
In a recent study Chou and colleagues used state of the art techniques to investigate conflict resolution (winning or losing bouts of aggression) in zebrafish, with a particular focus on the habenula (Chou et al., 2016). The authors used calcium imaging to visualise neural activity and uncovered differential activation of the habenula circuitry. Fish which either won a fight or were not exposed to aggression showed calcium signals in the lateral dorsal habenula and dorsal IPN, whereas fish who lost a fight – “losers” – showed medial dorsal habenul and ventral IPN activity.
In a next set of experiments, Chou et al used genetic tricks (Gal4:UAS lines targeted to specific neurons driving expression of tetanus neurotoxin to block firing) to silence habenula activity and then watched fish fight. Silencing of the lateral dorsal habenula increased the chances that a fish would lose a fight whereas blocking medial lateral habenula activity increased the number of fights won. In all cases examined there were no changes to other behaviours including locomotion and anxiety; differential habenula activation really does seem to underlie fighting ability!
Taken in a wider context, this is an impressive study because the habenula-IPN-DTA circuit seems to act a switch for aggression. It seems likely that a balance between activation of two pathways – either at the level of the habenula itself, or between neurons in the IPN – controls the outcome of social interactions. Alterations to the habenula have been linked to several psychiatric disorders such as major depression, ADHD and schizophrenia. Further studies looking at lateralised brain activity may even shed light on the symptoms of some human diseases.

In his most famous book, Walden, the American author and naturalist Henry David Thoreau wrote that “many men go fishing all of their lives, without knowing it is not fish they are after”. Thus, one of the difficulties encountered when studying behaviour is to understand their underlying motivation. What makes some animals aggressive and other not when faced with the same situation? How does the brain process stimuli to generate an appropriate behavioural response?

A recent study by Golden and colleagues (Golden et al., 2016) has investigated this question in mice. They combined the resident-intruder assay (a rodent aggression test) with a condition place preference (CPP) test for reward behaviour. The resident-intruder test measures the response of a mouse towards an intruder in its home cage. In this case, male CD-1 mice were allowed to interact with a subordinate C57BL/BJ intruder. Aggressive contact was recorded as the latency for CB-1 mice to attack. Interestingly, about 70% of CD-1 mice were aggressive in this setup (AGGs) and 30% were non-aggressive (NONs). The CPP pairs a neutral stimulus (in this case one side of the home cage) with a conditioned stimulus – the intruder mouse. If the conditioned stimulus is rewarding then test animals spend more time on side of the cage where it was encountered. Here, CD-1 were permitted to interact with C57BL/6J intruders on one side of the CPP setup, whereas the non-conditioned side was empty. AGGs show a positive change in preference under these conditions where NONs showed aversion – they kept away from the intruder. This suggests that AGGs find the aggressive stimulation rewarding and actively seek out the interaction with C57BL/6J.

The authors next examined the neural circuits that control this behaviour with a focus on the connection between the basal forebrain and lateral habenula. During formation of aggression mediated-CPP AGGs show increased forebrain activation (in the nucleus accumbens, diagonal band and lateral septum) with a simultaneous reduction in habenula activity. Next, state of the art optogenetic techniques were used to either activate or inhibit the habenula. Stimulation of the forebrain-habenula circuit in NONs caused a positive change in place preference, whereas inhibition of this circuit in AGGs decreased CPP: the valency of the C57BL/6J stimulus mouse had changed! Importantly, optogenetic stimulation did not alter other social behaviours, although both the intensity of aggression and the rewarding properties of cocaine were increased.

This is exciting research that has possible translational potential to other species. The habenula (and in particular its interaction with the forebrain) appears to be important in processing of stimuli that can elicit aggression. In humans, deep brain stimulation of the basal forebrain and habenula has already been achieved suggesting a possible future treatment for pathological aggression.