Sebastian Haesler

During odor-guided navigation, animals combine sensory cues with spatial information to make behavioral choices. The integration of olfactory and spatial information involves a highly interconnected olfactory-hippocampal circuit, yet it remains unclear whether task-relevant odor representations are distributed across this network or emerge within specialized nodes. Moreover, decisions in natural environments often do not just depend on physical stimulus properties, but on higher-order, categorical stimulus features. Here, we trained freely moving mice to learn such an abstract decision rule, whereby odor novelty, rather than odor identity, determined reward location. Simultaneous recordings from posterior piriform cortex, lateral entorhinal cortex (LEC), CA1, and dentate gyrus revealed that neural population activity across the network was dominated by spatial task variables. During odor sampling, the piriform cortex and LEC encoded odor identity and novelty. Remarkably, only the piriform cortex maintained stable novelty representations across behavioral epochs, from odor sampling to reward approach. These findings identify the posterior piriform as a key hub for maintaining abstract, task-relevant representations that link sensory cues to spatial decisions.

Perception relies on the neural representation of sensory stimuli. Primary sensory cortical representations have been extensively studied, but how sensory information propagates to memory-related multisensory areas has not been well described. We studied this question in the olfactory cortico-hippocampal pathway in mice. We recorded single units in the anterior olfactory nucleus (AON), the anterior piriform cortex (aPCx), the lateral entorhinal cortex (LEC), the hippocampal CA1 subfield, and the subiculum (SUB) while animals performed a non-associative learning paradigm involving novel and familiar stimuli. In the AON, neurons were broadly tuned to different chemicals, and their responses were strongly modulated by experience. From the AON to hippocampal structures, the selectivity of neurons for specific odorants increased, concurrent with the development of population-level odor representations, which became independent of novelty and familiarity. While both stimulus identity and experience were thus reflected in all regions, their neural representations progressively separated. Our findings provide a potential mechanism for how sensory representations are transformed to support stimulus identification and implicit memories.

Perception relies on the neural representation of sensory stimuli. Primary sensory cortical representations have been extensively studied, but how sensory information propagates to memory-related multisensory areas has not been well described. We studied this question in the olfactory cortico-hippocampal pathway in mice. We recorded single units in the anterior olfactory nucleus (AON), the anterior piriform cortex (aPCx), lateral entorhinal cortex (LEC), the hippocampal CA1 subfield, and the subiculum (SUB) while animals performed a non-associative learning paradigm involving novel and familiar stimuli. In the AON, neurons were broadly tuned to different chemicals, and their responses were strongly modulated by experience. From the AON to hippocampal structures, the selectivity of neurons for specific odorants increased, concurrent with the development of population-level odor representations, which became independent of novelty and familiarity. While both stimulus identity and experience were thus reflected in all regions, their neural representations progressively separated. Our findings provide a potential mechanism for how sensory representations are transformed to support stimulus identification and implicit memories.

Novel stimuli have a profound impact on brain function and behavior. They evoke attention, arousal and sensory exploration and induce synaptic plasticity in brain regions related to learning and memory. Many of these effects have been attributed to novelty-evoked activation of the dopaminergic midbrain and dopamine (DA) release in major projection targets in the striatum. However, it remains controversial if individual DA neurons respond to novel stimuli. To address this question, we recorded and manipulated DA neurons in mice exposed to novel and familiar odors while monitoring orienting behaviors including exploratory sniffing, facial movements, and pupil dilation. We found that DA neurons were activated by orienting behaviors, rather than by novelty itself. Moreover, their activity was causally involved in generating the orienting responses. Finally, we identified a major input region to the dopaminergic midbrain which couples orienting to DA firing. Activity in the mediodorsal pons (mdPons) correlated tightly with sniffing and facial movements. Consequently, optogenetic stimulation of glutamatergic mdPons neurons induced both orienting and DA firing. Our findings suggest that DA neurons do not respond to novelty per se but are activated through descending glutamatergic projections from the mdPons. This mechanism links salient sensory events to DA release, providing a basis for novelty-evoked exploration and plasticity.

The spontaneous exploratory reaction to novel stimuli reflects a fundamental form of curiosity, which is widely observed in the animal kingdom. How sensory systems mediate the recognition of novel stimuli to evoke exploration is not well understood. To address this question, we presented novel and familiar olfactory stimuli to head-restrained mice, while measuring novelty-evoked exploratory behaviors. In parallel, we recorded neural activity in primary olfactory cortical structures, the anterior olfactory nucleus (AON) or the anterior piriform cortex (aPCx). Novelty strongly modulated odor responses in the AON, but only weakly in the aPCx. Pharmacological and chemogenetic inactivation of the AON but not the aPCx disrupted exploratory responses. During long-term habituation over multiple days, sensory representations were drifting in the AON whereas they became stable within one day in the aPCx. Our findings suggest that AON and aPCx play distinct roles in novelty-evoked exploration. While the AON mediates the immediate reaction to novel stimuli, the aPCx exhibits stable stimulus representations, consistent with supporting odor memory.

Murayama and Jach point out that we do not sufficiently understand the constructs and mental computations underlying higher-order motivated behaviors. Although this may be generally true, we would like to add and contribute to the discussion by outlining how interdisciplinary research on novelty-evoked exploration has advanced the study of learning and curiosity.

Perception relies on the neural representation of sensory stimuli. Primary sensory cortical representations have been extensively studied, but how sensory information propagates to memory-related multisensory areas has not been well described. We studied this question in the olfactory cortico-hippocampal pathway in mice. We recorded single units in the anterior olfactory nucleus (AON), the anterior piriform cortex (aPCx), lateral entorhinal cortex (LEC), the hippocampal CA1 subfield, and the subiculum (SUB) while animals performed a non-associative learning paradigm involving novel and familiar stimuli. In the AON, neurons were broadly tuned to different chemicals, and their responses were strongly modulated by experience. From the AON to hippocampal structures, the selectivity of neurons for specific odorants increased, concurrent with the development of population-level odor representations, which became independent of novelty and familiarity. While both stimulus identity and experience were thus reflected in all regions, their neural representations progressively separated. Our findings provide a potential mechanism for how sensory representations are transformed to support stimulus identification and implicit memories.

Two‐photon polymerization (TPP) is an additive manufacturing technique with micron‐scale resolution that is rapidly gaining ground for a range of biomedical applications. TPP is particularly attractive for the creation of microscopic three‐dimensional structures in biocompatible and noncytotoxic resins. Here, TPP is used to develop microfluidic interfaces which provide chronic fluidic access to the brain of preclinical research models. These microcatheters can be used for either convection‐enhanced delivery (CED) or for the repeated collection of liquid biopsies. In a brain phantom, infusions with the micronozzle result in more localized distribution clouds and lower backflow compared to a control catheter. In mice, the delivery interface enables faster, more precise, and physiologically less disruptive fluid injections. A second microcatheter design enables repeated, longitudinal sampling of cerebrospinal fluid (CSF) over time periods as long as 250 days. Moreover, further in vivo studies demonstrate that the blood‐CSF barrier is intact after chronic implantation of the sampling interface and that samples are suitable for downstream molecular analysis for the identification of nucleic acid‐ or peptide‐based biomarkers. Ultimately, the versatility of this fabrication technique implies a great translational potential for simultaneous drug delivery and biomarker tracking in a range of human neurological diseases.

Electrode grids are used in neuroscience research and clinical practice to record electrical activity from the surface of the brain. However, existing passive electrocorticography (ECoG) technologies are unable to offer both high spatial resolution and wide cortical coverage, while ensuring a compact acquisition system. The electrode count and density are restricted by the fact that each electrode must be individually wired. This work presents an active micro‐electrocorticography (µECoG) implant that tackles this limitation by incorporating metal oxide thin‐film transistors (TFTs) into a flexible electrode array, allowing to address multiple electrodes through a single shared readout line. By combining the array with an incremental‐ΔΣ readout integrated circuit (ROIC), the system is capable of recording from up to 256 electrodes virtually simultaneously, thanks to the implemented 16:1 time‐division multiplexing scheme, offering lower noise levels than existing active µECoG arrays. In vivo validation is demonstrated acutely in mice by recording spontaneous activity and somatosensory evoked potentials over a cortical surface of ≈8×8 mm². The proposed neural interface overcomes the wiring bottleneck limiting ECoG arrays, holding promise as a powerful tool for improved mapping of the cerebral cortex and as an enabling technology for future brain‐machine interfaces.