رویکردهای تجربی ارزیابی وزوز در مدل‌های حیوانی: روش‌ها، چالش‌ها و چشم‌اندازها

"Experimental Approaches to Assessing Tinnitus in Animal Models: Methods, Challenges, and Perspectives"

Background and aimes: Tinnitus, defined as the sense of sound when no external stimulation is present, is a prevalent auditory system impairment that impacts the quality of life of millions of individuals across the world. Whereas clinical and medical research has made significant progress, the exact brain mechanisms and etiology of tinnitus remain unclear. Although tinnitus can be better understood and diagnosed through human studies, there are several limitations related to these approaches that make animal models indispensable for studying pathophysiology, assessing treatments, and studying neurological changes. These limitations include not being able to control biological and environmental variables and the difficulty of implementing invasive interventions. Applying acoustic and pharmacological stimuli, carefully controlling laboratory settings, and studying the direct effects of interventions on peripheral and central auditory pathways are all made possible through the use of animals. Therefore, in order to evaluate tinnitus in animal models, we explain and contrast behavioral training techniques with electrophysiological tests in this study.

Materials and Methods: A literature search was conducted in PubMed, Google Scholar, and Web of Science databases for studies published between 1988 and 2025. Keywords such as "animal model of tinnitus", "auditory attention", "GPIAS", "behavioral assessment", "ABR", "salicylate", "noise", "active avoidance", "distress", "anxiety", "operant behavioral methods" and "Auditory brainstem response" were utilized. The selection of articles was based on a number of criteria, such as the evaluation of tinnitus using behavioral or electrophysiological techniques and validated animal models.

Results: Since Jastreboffe t al. (1988) produced the first behavioral model, several techniques have been developed to evaluate tinnitus in animals. These techniques primarily rely on active conditioning through the use of punishment (such as: conditioned lick suppression procedures, conditioned lever pressing procedure, conditioned Two-Choice Left/Right Procedure, Active Avoidance) or motivation (i.e. T Water Maze Model, conditioned liquid reward procedures). In the conditioned lick suppression procedures, the animal is trained to cease licking when the environment is silent; if not, it receives a mild electric shock. Later on, following tinnitus induction, a tinnitus index is calculated based on the degree of behavioral suppression. The modified version of this model involves conditioning following tinnitus induction; since tinnitus is associated with electric shock, it is feasible to evaluate tinnitus pitch and emotional responses to it. While lick suppression procedure and the conditioned lever pressing method are comparable, the latter allows for the evaluation of chronic tinnitus months after initial induction. The distinction between sound stimuli and quiet is also used by the conditioned Two-Choice Left/Right Procedure and the T Water Maze Model, which enable researchers to carefully evaluate sound direction and the perception of unilateral or bilateral tinnitus. Giving the animal a liquid reward rather than punishment lowers their stress levels, enables ongoing evaluation, and increases their sensitivity to tinnitus cues. Pre-pulse inhibition (PPI) and gap pre-pulse inhibition of acoustic startle (GPIAS), two tests based on the acoustic startle response, have recently been developed as objective behavioral methods to evaluate tinnitus. These techniques are more convenient than conditioning tests because they do not require for extensive training, complicated motivation, or deprivation of food or drink. Tinnitus can be distinguished from hyperacusis, hearing loss, and temporal processing disorder using a combination of GPIAS and PPI outcomes. However, variability in responses and the requirement for large sample sizes in GPIAS led to the increased use of auditory electrophysiological assessments such as auditory brainstem response (ABR), middle latency response (MLR) and late latency response (LLR) as objective tools to confirm tinnitus (especially salicylate-induced tinnitus). In the past, ABR has been employed as a sensitive and efficient method to evaluate the threshold and function of central and peripheral auditory pathways in tinnitus animal models. An increase in hearing thresholds and a decrease in sensory input are indicated by a decrease in wave I's amplitude in the ABR test. However, following the generation of salicylate-induced tinnitus, the central waves (II–V) show increased amplitude and decreased latency, indicating excessive activation of auditory circuits. Moreover, some studies have explored the cognitive and emotional aspects of tinnitus in animal models, aiming to better understand the psychological responses to tinnitus. In addition, in an effort to gain a better understanding of the psychological reactions to tinnitus, a few research have investigated the emotional and cognitive components of the complaint in animal models, such as auditory attention,anxiety, depression, social interaction and aggressive behavior.

Conclusion: All things considered, combining behavioral, electrophysiological, and cognitive indicators could be essential for creating more precise animal models as well as developing focused treatment plans, such as pharmacological and cognitive-behavioral methods, for tinnitus and the negative effects that go along with it.