Testing behavioral influences on auditory gating in the

3.1.2.1 Auditory discrimination learning in the shuttle-box

A behavioral task that encompasses at least two of the mentioned state-variables, namely attention and stress, shown to influence gating, is auditory discrimination learning in a Go/NoGo paradigm in the shuttle-box. Within this task gerbils learn to differentiate the modulation direction of FM tones and are even able to transfer the category of modulation direction to novel stimuli (Wetzel et al., 1998). Within a two-compartmental shuttle-box, divided by a small hurdle, animals indicate a successful discrimination by changing the compartment as response to the presentation of the “Go”

conditioned stimulus (CS+) (in this case frequency upward modulated tones)

but suppressing a shuttle-response as reaction to the “NoGo” conditioned stimulus (CS-) (a frequency downward modulated tone). If, on CS+ trials, the animals fail to cross the hurdle within a certain time window, they receive a mild foot-shock and the trials are scored as “miss”; conversely if the animals shuttle during a CS- trial they are punished as well (“false alarm”). The initial learning in the shuttle-box is of Pavlovian nature when the animals learn to associate the conditioned stimulus (CS) with the unconditioned stimulus (US), the foot shock (Cain & LeDoux, 2008). Within this phase animals normally overcome their anxiety and adopt an escape strategy in which they shuttle after having received the foot-shock. Simultaneously, animals acquire the discrimination between the CS+ and CS- conditional stimuli, and learn to suppress shuttling in response to the CS-, which would be followed by a foot shock as well. Once the animals transit from escape reactions to an active avoidance, i.e. changing the compartment as response to the CS+

(CR: conditioned response), a strong association of CS-US has been formed and the Go/NoGo reaction strategy has been developed.

3.1.2.2 Putative involvement of the auditory cortex and the ventral striatum in the Go/NoGo auditory discrimination task

Ohl et al. (1999) have shown that the auditory cortex plays a central role in discrimination learning of FM tones, but not pure tones. Bilateral ablation of the auditory cortex corrupted the acquisition of the discrimination in the first place, but also impaired the retention of the FM categorization by a marked increase in false alarm responses in pre-trained animals. High-resolution electro-corticographical recordings in this area revealed that the formation of “rising” and “falling” FM tone category is accompanied by a sudden change in behavior and a marked change in the dynamics of cortical stimulus representation (Ohlet al.,2001).

Sound specific auditory learning involves a tonotopically organized cortico-thalamic cortico-collicular loop that is modulated mainly via cholinergic but also serotonergic and dopaminergic transmission (reviewed in Xiong et al., 2009). Learning in the sweep direction discrimination task, in particular, has

been shown to depend on dopamine (DA) signaling and protein synthesis within the auditory cortex (Kraus et al., 2002; Schicknick et al., 2012).

Auditory fear learning involves both, the lemniscal pathway (involving the ventral division of the medial geniculate body in the thalamus) and non-lemniscal circuit (involving the medial division of the medial geniculate body), but the perpetuation of discriminative fear and its extinction depended mainly on an intact non-lemniscal pathway that projects directly from the thalamus to the amygdala (Antunes & Moita,2010).

On the other hand, amygdala and striatum appear to complement one another in procedures of appetitive and aversive conditioning (Delgado et al., 2008). Two-way active avoidance acquisition, for example, has been demonstrated to depend upon dopamine signaling in the amygdala, but also the entire striatum (Darvas et al., 2011). Using gene therapy to selectively restore DA signaling, Darvaset al. (2011) also showed that after prolonged training (possibly after habit formation) only dopamine in the striatum was needed to retain the active avoidance behavior. This finding underlines the striatum’s central position in stimulus-response (SR) behavior.

It has to be noted however, that the shift from “goal-directed” to “stimulus-response” behavior, mediated by the associative and sensorimotor striatal regions respectively, is most probably continuous and the process of habit formation and temporal involvement of striatal regions herein are still not clear (reviewed by Adamset al.,2001;Ashby et al.,2010).

The ventral part of this large brain structure has been mostly implicated in goal-directed behavior, in which the calculations of expected reward values and actual response outcomes (the “prediction error”) become fundamental to decision making and action selection. Reinforcement theories that involve striatal activities, for instance by calculating this prediction error, oftentimes applied appetitive procedures. This complicates the image on shuttle-box learning, by posing the question if the avoidance of an aversive outcome can be regarded as rewarding itself. In studies involving human subjects the medial orbitofrontal cortex – a structure also implicated in prediction error processing – was equally recruited during money loss and during the reception of a monetary reward (Kim et al., 2006). There is also good

evidence that aversive conditioning involves the ventral striatum and that negative prediction errors are coded by dopaminergic signaling similar to appetitive reward predictions (reviewed inDelgadoet al.,2008).

Hence there is proof that the ventral striatum is involved in acquiring the auditory cue-significance associated with CS+ and CS- respectively in the FM tone discrimination task in the shuttle-box regardless of its primary aversive nature. Furthermore, in the ventral striatum, appropriate response selection would be fine-tuned according to reinforcement theories. The task is also tightly dependent on the auditory cortex, both during the acquisition and the retention (Ohl et al.,1999). An interplay between both brain areas appears most likely.

Reports on the interaction between auditory cortex and the ventral striatum are sparsely found. Popescu et al. (2009) investigated how gamma oscillations couple the basolateral amygdala and the ventral striatum during appetitive auditory discrimination learning in cats and also recorded from the auditory cortex. However they could not show any learning related changes in the gamma-coupling of cortex and striatum; on the other hand amygdalostriatal interactions in the gamma frequency range markedly increased during the course of learning. In a most recent study,Znamenskiy

& Zador (2013) manipulated corticostriatal projections from the auditory cortex to the “auditory” caudal striatum using optogenetic-techniques. They could show that activation or inactivation of direct cortico-striatal projections were able to influence response bias and reaction times on a two-way auditory choice discrimination task.

Conclusively auditory cortico-striatal projections transmit sound information that these rats utilized to make decisions. If auditory gating has a role in this rather complex task is unclear. The other way round, how auditory gating could be affected by the auditory discrimination task is indistinct:

variables of selective attention, mild stress and the formation of (procedural) memories all loom within the task.

According to the aforementioned facts, the following hypotheses related to the impact of discrimination training on auditory gating were put forward:

1. Using a train of identical frequency modulated tones as CS, attention needs to be paid only to the first tone (as minimum requirement) to identify the adequate response action, hence on average gating should be intact. It appears possible, however, that during the very initial sessions, when a proper CS+/CS- discrimination has not been attained, yet, attention on the single tones of a train could be elevated and gating diminished. Therefore, the timepoint at which animals properly discriminated between CS+ and CS- was determined, and comparison of AEP gating values before and after this timepoint have been made.

If the task required additional attentional resources, gating should initially have been diminished. Also possible differences between the subcomponents were to be investigated to identify putative pre-attentiveness of single subcomponents.

2. Stress should increase during the first sessions in the avoidance paradigm, then gradually decrease as performance goes up (Johnson

& Adler, 1993), escape reactions become true avoidances and the animals receive less shocks: hence gating scores could have been negatively correlated with stresslevel. A correlation analysis with performance and gating scores was calculated to clarify this.

3. Finally, it was of interest if discrimination training strengthened or modulated the auditory cortex – ventral striatum interaction. Therefore a comparison of phase-locking before and after the discrimination training had been calculated.