Acquisition of non-olfactory encoding improves odour discrimination in olfactory cortex.

Olfaction is influenced by contextual factors, past experiences, and the animal's internal state. Whether this information is integrated at the initial stages of cortical odour processing is not known, nor how these signals may influence odour encoding. Here we revealed multiple and diverse non-olfactory responses in the primary olfactory (piriform) cortex (PCx), which dynamically enhance PCx odour discrimination according to behavioural demands. We performed recordings of PCx neurons from mice trained in a virtual reality task to associate odours with visual contexts to obtain a reward. We found that learning shifts PCx activity from encoding solely odours to a regime in which positional, contextual, and associative responses emerge on odour-responsive neurons that become mixed-selective. The modulation of PCx activity by these non-olfactory signals was dynamic, improving odour decoding during task engagement and in rewarded contexts. This improvement relied on the acquired mixed-selectivity, demonstrating how integrating extra-sensory inputs in sensory cortices can enhance sensory processing while encoding the behavioural relevance of stimuli.

Participation of the spleen in the neuroinflammation after pilocarpine-induced status epilepticus: implications for epileptogenesis and epilepsy.

Epilepsy, a chronic neurological disorder characterized by recurrent seizures, affects millions of individuals worldwide. Despite extensive research, the underlying mechanisms leading to epileptogenesis, the process by which a normal brain develops epilepsy, remain elusive. We, here, explored the immune system and spleen responses triggered by pilocarpine-induced status epilepticus (SE) focusing on their role in the epileptogenesis that follows SE. Initial examination of spleen histopathology revealed transient disorganization of white pulp, in animals subjected to SE. This disorganization, attributed to immune activation, peaked at 1-day post-SE (1DPSE) but returned to control levels at 3DPSE. Alterations in peripheral blood lymphocyte populations, demonstrated a decrease following SE, accompanied by a reduction in CD3+ T-lymphocytes. Further investigations uncovered an increased abundance of T-lymphocytes in the piriform cortex and choroid plexus at 3DPSE, suggesting a specific mobilization toward the Central Nervous System. Notably, splenectomy mitigated brain reactive astrogliosis, neuroinflammation, and macrophage infiltration post-SE, particularly in the hippocampus and piriform cortex. Additionally, splenectomized animals exhibited reduced lymphatic follicle size in the deep cervical lymph nodes. Most significantly, splenectomy correlated with improved neuronal survival, substantiated by decreased neuronal loss and reduced degenerating neurons in the piriform cortex and hippocampal CA2-3 post-SE. Overall, these findings underscore the pivotal role of the spleen in orchestrating immune responses and neuroinflammation following pilocarpine-induced SE, implicating the peripheral immune system as a potential therapeutic target for mitigating neuronal degeneration in epilepsy.

Epileptogénesis y corteza piriforme: entendiendo a la epilepsia del lóbulo temporal más allá del hipocampo / Epileptogenesis and the piriform cortex: understanding temporal lobe epilepsy beyond the hippocampus

Introducción: Con la experiencia de los registros electroencefalográficos invasivos y el fracaso quirúrgico después de la cirugía, se ha hecho evidente que la epilepsia del lóbulo temporal es mucho más compleja de lo que se creía, y en la actualidad es considerada una enfermedad de redes anatomofuncionales y no de lesiones estructurales. Contenido: La información neurofisiológica e imagenológica actual permite concluir que en esta epilepsia están involucradas varias redes neuronales temporales y extratemporales que contribuyen a la extensión de la zona epileptógena. Una forma de entender el concepto de red epiléptica en la epilepsia del lóbulo temporal es a partir del conocimiento de la corteza piriforme. Varios estudios clínicos han mostrado que en pacientes con epilepsia del lóbulo temporal asociada a esclerosis hipocampal existe una disfunción interictal del procesamiento olfatorio que es más significativa, en comparación con pacientes con epilepsia focal extrahipocampal y controles sanos. Esta alteración es, probablemente, la consecuencia de una red neuronal disfuncional que se extiende más allá del hipocampo y que afecta a otras estructuras cercanas, incluida la corteza piriforme. Conclusión: En este artículo llevamos a cabo una revisión narrativa de la literatura con el objetivo de establecer un vínculo entre la corteza piriforme y la epileptogénesis del lóbulo temporal, y demostramos que esta enfermedad es la consecuencia de una disfunción de redes neuronales que no depende exclusivamente de una anormalidad estructural en el hipocampo o en estructuras cercanas.

Introduction: With the experience of invasive EEG recordings and surgical failure after surgery, it has become clear that temporal lobe epilepsy is much more complex than previously thought, and currently, is conceptualized as a disease of anatomical networks instead of structural lesions. Content: The current neurophysiological and imaging information allows us to conclude that several temporal and extratemporal anatomical networks are involved in this type of epilepsy. One way of understanding the concept of the epileptic network in temporal lobe epilepsy is from the knowledge of the piriform cortex. Several clinical studies have shown that in patients with temporal lobe epilepsy associated with hippocampal sclerosis exists an interictal dysfunction of olfactory processing that is more significant compared to patients with focal extra-hippocampal epilepsy and healthy controls. This alteration is probably the consequence of a dysfunctional neural network that extends beyond the hippocampus and affects other nearby structures, including the piriform cortex. Conclusion: In this article, we carry out a narrative review of the literature with the aim of establishing a link between the piriform cortex and temporal lobe epileptogenesis, demonstrating that this disease is the consequence of a dysfunctional network that does not depend exclusively of a hippocampal structural abnormality.

Mechanisms and functions of respiration-driven gamma oscillations in the primary olfactory cortex.

Gamma oscillations are believed to underlie cognitive processes by shaping the formation of transient neuronal partnerships on a millisecond scale. These oscillations are coupled to the phase of breathing cycles in several brain areas, possibly reflecting local computations driven by sensory inputs sampled at each breath. Here, we investigated the mechanisms and functions of gamma oscillations in the piriform (olfactory) cortex of awake mice to understand their dependence on breathing and how they relate to local spiking activity. Mechanistically, we find that respiration drives gamma oscillations in the piriform cortex, which correlate with local feedback inhibition and result from recurrent connections between local excitatory and inhibitory neuronal populations. Moreover, respiration-driven gamma oscillations are triggered by the activation of mitral/tufted cells in the olfactory bulb and are abolished during ketamine/xylazine anesthesia. Functionally, we demonstrate that they locally segregate neuronal assemblies through a winner-take-all computation leading to sparse odor coding during each breathing cycle. Our results shed new light on the mechanisms of gamma oscillations, bridging computation, cognition, and physiology.

The cerebral cortex is the most recently evolved region of the mammalian brain. There, millions of neurons can synchronize their activity to create brain waves, a series of electric rhythms associated with various cognitive functions. Gamma waves, for example, are thought to be linked to brain processes which require distributed networks of neurons to communicate and integrate information. These waves were first discovered in the 1940s by researchers investigating brain areas involved in olfaction, and they are thought to be important for detecting and recognizing smells. Yet, scientists still do not understand how these waves are generated or what role they play in sensing odors. To investigate these questions, González et al. used a battery of computational approaches to analyze a large dataset of brain activity from awake mice. This revealed that, in the cortical region dedicated to olfaction, gamma waves arose each time the animals completed a breathing cycle ­ that is, after they had sampled the air by breathing in. Each breath was followed by certain neurons relaying olfactory information to the cortex to activate complex cell networks; this included circuits of cells known as feedback interneurons, which can switch off weakly activated neurons, including ones that participated in activating them in the first place. The respiration-driven gamma waves derived from this 'feedback inhibition' mechanism. Further work then examined the role of the waves in olfaction. Smell identification relies on each odor activating a unique set of cortical neurons. The analyses showed that gamma waves acted to select and amplify the best set of neurons for representing the odor sensed during a sniff, and to quieten less relevant neurons. Loss of smell is associated with many conditions which affect the brain, such as Alzheimer's disease or COVID-19. By shedding light on the neuronal mechanisms that underpin olfaction, the work by González et al. could help to better understand how these impairments emerge, and how the brain processes other types of complex information.

The maturational characteristics of the GABA input in the anterior piriform cortex may also contribute to the rapid learning of the maternal odor during the sensitive period.

During the first ten postnatal days (P), infant rodents can learn olfactory preferences for novel odors if they are paired with thermo-tactile stimuli that mimic components of maternal care. After P10, the thermo-tactile pairing becomes ineffective for conditioning. The current explanation for this change in associative learning is the alteration in the norepinephrine (NE) inputs from the locus coeruleus (LC) to the olfactory bulb (OB) and the anterior piriform cortex (aPC). By combining patch-clamp electrophysiology and computational simulations, we showed in a recent work that a transitory high responsiveness of the OB-aPC circuit to the maternal odor is an alternative mechanism that could also explain early olfactory preference learning and its cessation after P10. That result relied solely on the maturational properties of the aPC pyramidal cells. However, the GABAergic system undergoes important changes during the same period. To address the importance of the maturation of the GABAergic system for early olfactory learning, we incorporated data from the GABA inputs, obtained from in vitro patch-clamp experiment in the aPC of rat pups aged P5-P7 reported here, to the model proposed in our previous publication. In the younger than P10 OB-aPC circuit with GABA synaptic input, the number of responsive aPC pyramidal cells to the conditioned maternal odor was amplified in 30% compared to the circuit without GABAergic input. When compared with the circuit with other younger than P10 OB-aPC circuit with adult GABAergic input profile, this amplification was 88%. Together, our results suggest that during the olfactory preference learning in younger than P10, the GABAergic synaptic input presumably acts by depolarizing the aPC pyramidal neurons in such a way that it leads to the amplification of the pyramidal neurons response to the conditioned maternal odor. Furthermore, our results suggest that during this developmental period, the aPC pyramidal cells themselves seem to resolve the apparent lack of GABAergic synaptic inhibition by a strong firing adaptation in response to increased depolarizing inputs.

Postnatal development of inhibitory synaptic transmission in the anterior piriform cortex.

The morphological and functional development of inhibitory circuit in the anterior piriform cortex (aPC) during the first three postnatal weeks may be crucial for the development of odor preference learning in infant rodents. As first step toward testing this hypothesis, we examined the normal development of GABAergic synaptic transmission in the aPC of rat pups during the postnatal days (P) 5-8 and 14-17. Whole cell patch-clamp recordings of layer 2/3 (L2/3) aPC pyramidal cells revealed a significant increase in spontaneous (sIPSC) and miniature (mIPSC) inhibitory postsynaptic current frequencies and a decrease in mIPSC rise and decay-time constant at P14-P17. Moreover, as the development of neocortical inhibitory circuit can be driven by sensory experience, we recorded sIPSC and mIPSC onto L2/3 aPC pyramidal cells from unilateral naris-occluded animals. Early partial olfactory deprivation caused by naris occlusion do not affected the course of age-dependent increase IPSC frequency onto L2/3 aPC pyramidal cell. However, this age-dependent increase of sIPSC and mIPSC frequencies were lower on aPC pyramidal cells ipsilateral to the occlusion side. In addition, the age-dependent increase in sIPSC frequency and amplitude were more pronounced on aPC pyramidal cells contralateral to the occlusion. While mIPSC kinetics were not affected by age or olfactory deprivation, at P5-P8, the sIPSC decay-time constant on aPC pyramidal cells of both hemispheres of naris-occluded animals were significantly higher when compared to sham. These results demonstrated that the GABAergic synaptic transmission on the aPC changed during postnatal development by increasing inhibitory inputs on L2/3 pyramidal cells, with increment in frequency of both sIPSC and mIPSC and faster kinetics of mIPSC. Our data suggested that the maturation of GABAergic synaptic transmission was little affected by early partial olfactory deprivation. These results could contribute to unravel the mechanisms underlying the development of odor processing and olfactory preference learning.

Progressive anticipation in behavior and brain activation of rats exposed to scheduled daily palatable food.

Scheduled and restricted access to a palatable snack, i.e. chocolate, elicits a brief and strong anticipatory activation and entrains brain areas related with reward and motivation. This behavioral and neuronal activation persists for more than 7days when this protocol is interrupted, suggesting the participation of a time-keeping system. The process that initiates this anticipation may provide a further understanding of the time-keeping system underlying palatable food entrainment. The aim of this study was to analyze how this entraining protocol starts and to dissect neuronal structures that initiate a chocolate-entrained activation. We assessed the development of anticipation of 5g of chocolate during the first 8days of the entrainment protocol. General activity of control and chocolate-entrained rats was continuously monitored with movement sensors. Moreover, motivation to obtain the chocolate was assessed by measuring approaches and interaction responses toward a wire-mesh box containing chocolate. Neuronal activation was determined with c-Fos in reward-related brain areas. We report a progressive increase in the interaction with a box to obtain chocolate parallel to a progressive neuronal activation. A significant anticipatory activation was observed in the prefrontal cortex on day 3 of entrainment and in the nucleus accumbens on day 5, while the arcuate nucleus and pyriform cortex reached significant activation on day 8. The gradual response observed with this protocol indicates that anticipation of a rewarding food requires repetitive and predictable experiences in order to acquire a temporal estimation. We also confirm that anticipation of palatable food involves diverse brain regions.

Involvement of cerebral nervous system areas and cytokines on antihyperalgesic and anti-inflammatory activities of Kielmeyera rugosa Choisy (Calophyllaceae) in rodents.

Kielmeyera rugosa is a medicinal plant known in Northeastern Brazil as 'pau-santo', and it is used in the treatment of several tropical diseases such as malaria, schistosomiasis, and leishmaniasis. We evaluated antihyperalgesic and anti-inflammatory activities of methanol stem extract of K. rugosa (MEKR) in mice. The mechanical hyperalgesia induced by carrageenan and tumor necrosis factor-alpha (TNF-α), prostaglandin E2 , and dopamine were assessed. We also investigated the anti-inflammatory effect of MEKR on carrageenan-induced pleurisy and paw edema. Ninety minutes after the treatment, the animals were submitted to an imunofluorescence for Fos protein. MEKR (100, 200, and 400 mg/kg; p.o.) inhibited the development of mechanical hypernociception and edema. MEKR significantly decreased TNF-α and interleukin 1ß levels in pleural lavage and suppressed the recruitment of leukocytes. MEKR (1, 10, and 100 mg/mL) did not produce cytotoxicity, determined using the methyl-thiazolyl-tetrazolium assay in vitro. The locomotor activity was not affected. MEKR activated significantly the bulb olfactory, piriform cortex, and periaqueductal gray of the central nervous system. Our results provide first time evidence to propose that MEKR attenuates mechanical hyperalgesia and inflammation, in part, through an activation of central nervous system areas, mainly the periaqueductal gray and piriform cortex areas.