Temporal encoding: Relative and absolute representations of time guide behavior.

Temporal information-processing is critical for adaptive behavior and goal-directed action. It is thus crucial to understand how the temporal distance between behaviorally relevant events is encoded to guide behavior. However, research on temporal representations has yielded mixed findings as to whether organisms utilize relative versus absolute judgments of time intervals. To address this fundamental question about the timing mechanism, we tested mice in a duration discrimination procedure in which they learned to correctly categorize tones of different durations as short or long. After being trained on a pair of target intervals, the mice were transferred to conditions in which cue durations and corresponding response locations were systematically manipulated so that either the relative or absolute mapping remained constant. The findings indicate that transfer occurred most readily when relative relationships of durations and response locations were preserved. In contrast, when subjects had to re-map these relative relations, even when positive transfer initially occurred based on absolute mappings, their temporal discrimination performance was impaired, and they required extensive training to re-establish temporal control. These results demonstrate that mice can represent experienced durations both as having a certain magnitude (absolute representation) and as being shorter or longer of the two durations (an ordinal relation to other cue durations), with relational control having a more enduring influence in temporal discriminations. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Ototoxicity and Platinum Uptake Following Cyclic Administration of Platinum-Based Chemotherapeutic Agents.

Cisplatin is a widely used anti-cancer drug used to treat a variety of cancer types. One of the side effects of this life-saving drug is irreversible ototoxicity, resulting in permanent hearing loss in many patients. In order to understand why cisplatin is particularly toxic to the inner ear, we compared the hearing loss and cochlear uptake of cisplatin to that of two related drugs, carboplatin and oxaliplatin. These three drugs are similar in that each contains a core platinum atom; however, carboplatin and oxaliplatin are considered less ototoxic than cisplatin. We delivered these three drugs to mice using a 6-week cyclic drug administration protocol. We performed the experiment twice, once using equimolar concentrations of the drugs and once using concentrations of the drugs more proportional to those used in the clinic. For both concentrations, we detected a significant hearing loss caused by cisplatin and no hearing loss caused by carboplatin or oxaliplatin. Cochlear uptake of each drug was measured using inductively coupled plasma mass spectrometry (ICP-MS) to detect platinum. Cochlear platinum levels were highest in mice treated with cisplatin followed by oxaliplatin, while carboplatin was largely excluded from the cochlea. Even when the drug doses were increased, cochlear platinum remained low in mice treated with oxaliplatin or carboplatin. We also examined drug clearance from the inner ear by measuring platinum levels at 1 h and 24 h after drug administration. Our findings suggest that the reduced cochlear platinum we observed with oxaliplatin and carboplatin were not due to increased clearance of these drugs relative to cisplatin. Taken together, our data indicate that the differential ototoxicity among cisplatin, carboplatin, and oxaliplatin is attributable to differences in cochlear uptake of these three drugs.