Principles of nociceptive coding in the anterior cingulate cortex.

The perception of pain is a multidimensional sensory and emotional/affective experience arising from distributed brain activity. However, the involved brain regions are not specific for pain. Thus, how the cortex distinguishes nociception from other aversive and salient sensory stimuli remains elusive. Additionally, the resulting consequences of chronic neuropathic pain on sensory processing have not been characterized. Using in vivo miniscope calcium imaging with cellular resolution in freely moving mice, we elucidated the principles of nociceptive and sensory coding in the anterior cingulate cortex, a region essential for pain processing. We found that population activity, not single-cell responses, allowed discriminating noxious from other sensory stimuli, ruling out the existence of nociception-specific neurons. Additionally, single-cell stimulus selectivity was highly dynamic over time, but stimulus representation at the population level remained stable. Peripheral nerve injury-induced chronic neuropathic pain led to dysfunctional encoding of sensory events by exacerbation of responses to innocuous stimuli and impairment of pattern separation and stimulus classification, which were restored by analgesic treatment. These findings provide a novel interpretation for altered cortical sensory processing in chronic neuropathic pain and give insights into the effects of systemic analgesic treatment in the cortex

Increased burst coding in deep layers of the ventral anterior cingulate cortex during neuropathic pain

Neuropathic pain induces changes in neuronal excitability and synaptic connectivity in deep layers of the anterior cingulate cortex (ACC) that play a central role in the sensory, emotional and affective consequences of the disease. However, how this impacts ACC in vivo activity is not completely understood. Using a mouse model, we found that neuropathic pain caused an increase in ACC in vivo activity, as measured by the indirect activity marker c-Fos and juxtacellular electrophysiological recordings. The enhanced firing rate of ACC neurons in lesioned animals was based on a change in the firing pattern towards bursting activity. Despite the proportion of ACC neurons recruited by noxious stimuli was unchanged during neuropathic pain, responses to noxious stimuli were characterized by increased bursting. Thus, this change in coding pattern may have important implications for the processing of nociceptive information in the ACC and could be of great interest to guide the search for new treatment strategies for chronic pain

Plasticity of Cortico-striatal Neurons of the Caudal Anterior Cingulate Cortex During Experimental Neuropathic Pain

Maladaptive neuronal plasticity is a main mechanism for the development and maintenance of pathological pain. Affective, motivational and cognitive deficits that are comorbid with pain involve cellular and synaptic modifications in the anterior cingulate cortex (ACC), a major brain mediator of pain perception. Here we use a model of neuropathic pain (NP) in male mice and ex-vivo electrophysiology to investigate whether layer 5 caudal ACC (cACC) neurons projecting to the dorsomedial striatum (DMS), a critical region for motivational regulation of behavior, are involved in aberrant neuronal plasticity. We found that while the intrinsic excitability of cortico-striatal cACC neurons (cACC-CS) was preserved in NP animals, excitatory postsynaptic potentials (EPSP) induced after stimulation of distal inputs were enlarged. The highest synaptic responses were evident both after single stimuli and in each of the EPSP that compose responses to trains of stimuli, and were accompanied by increased synaptically-driven action potentials. EPSP temporal summation was intact in ACC-CS neurons from NP mice, suggesting that the plastic changes were not due to alterations in dendritic integration but rather through synaptic mechanisms. These results demonstrate for the first time that NP affects cACC neurons that project to the DMS and reinforce the notion that maladaptive plasticity of the cortico-striatal pathway may be a key factor in sustaining pathological pain.Fil: Trujillo, María Jesús. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Ilarraz, Constanza. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Kasanetz, Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentin

Disruption of the two-state membrane potential of striatal neurones during cortical desynchronisation in anaesthetised rats

In anaesthetised animals, the very negative resting membrane potential of striatal spiny neurones (down state) is interrupted periodically by depolarising plateaux (up states) which are probably driven by excitatory input. In the absence of active synaptic input, as occurs in vitro, potassium currents hold the membrane potential of striatal spiny neurones in the down state. Because striatal spiny neurones fire action potentials only during the up state, these plateau depolarisations have been perceived as enabling events that allow information processing through cerebral cortex-basal ganglia circuits. Recent studies have demonstrated that the robust membrane potential fluctuation of spiny neurones is strongly correlated to the slow electroencephalographic rhythms that are typical of slow wave sleep and anaesthesia. To further understand the impact of cortical activity states on striatal function, we studied the membrane potential of striatal neurones during cortical desynchronised states. Simultaneous in vivo recordings of striatal neurones and the electrocorticogram in urethane-anaesthetised rats revealed that rhythmic alternation between up and down states was disrupted during episodes of spontaneous or induced cortical desynchronisation. Instead of showing robust two-state fluctuations, the membrane potential of striatal neurones displayed a persisting depolarised state with fast, low-amplitude modulations. Spiny neurones remained in this persistent up state until the cortex resumed ∼1 Hz synchronous activity. Most of the recorded neurones exhibited a low firing probability, irrespective of the cortical activity state. Time series analysis failed to reveal significant correlations between the membrane potential of striatal neurones and the desynchronised electrocorticogram. Our results suggest that during cortical desynchronisation continuous uncorrelated excitatory input sustains the membrane potential of striatal neurones in a persisting depolarised state, but that substantial additional input is necessary to impel the neurones to threshold. Our data support that the prevailing cortical activity state determines the duration of the enabling depolarising events that take place in striatal spiny neurones

Brain oscillations, medium spiny neurons, and dopamine

1. The striatum is part of a multisynaptic loop involved in translating higher order cognitive activity into action. The main striatal computational unit is the medium spiny neuron, which integrates inputs arriving from widely distributed cortical neurons and provides the sole striatal output. 2. The membrane potential of medium spiny neurons’ displays shifts between a very negative resting state (down state) and depolarizing plateaus (up states) which are driven by the excitatory cortical inputs. 3. Because striatal spiny neurons fire action potentials only during the up state, these plateau depolarizations are perceived as enabling events that allow information processing through cerebral cortex – basal ganglia circuits. In vivo intracellular recording techniques allow to investigate simultaneously the subthreshold behavior of the medium spiny neuron membrane potential (which is a “reading” of distributed patterns of cortical activity) and medium spiny neuron firing (which is an index of striatal output). 4. Recent studies combining intracellular recordings of striatal neurons with field potential recordings of the cerebral cortex illustrate how the analysis of the input–output transformations performed by medium spiny neurons may help to unveil some aspects of information processing in cerebral cortex – basal ganglia circuits, and to understand the origin of the clinical manifestations of Parkinson’s disease and other neurologic and neuropsychiatric disorders that result from alterations in dopamine-dependent information processing in the cerebral cortex – basal ganglia circuits.Fil: Murer, Mario Gustavo. Universidad de Buenos Aires. Facultad de Medicina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: Tseng, Kuei Y.. Universidad de Buenos Aires. Facultad de Medicina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: Kasanetz, Fernando. Universidad de Buenos Aires. Facultad de Medicina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: Belluscio, Mariano Andres. Universidad de Buenos Aires. Facultad de Medicina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: Riquelme, Luis Alberto. Universidad de Buenos Aires. Facultad de Medicina; Argentin

Enhanced Functional Activity of the Cannabinoid Type-1 Receptor Mediates Adolescent Behavior

Adolescence is characterized by drastic behavioral adaptations and comprises a particularly vulnerable period for the emergence of various psychiatric disorders. Growing evidence reveals that the pathophysiology of these disorders might derive from aberrations of normal neurodevelopmental changes in the adolescent brain. Understanding the molecular underpinnings of adolescent behavior is therefore critical for understanding the origin of psychopathology, but the molecular mechanisms that trigger adolescent behavior are unknown. Here, we hypothesize that the cannabinoid type-1 receptor (CB1R) may play a critical role in mediating adolescent behavior because enhanced endocannabinoid (eCB) signaling has been suggested to occur transiently during adolescence. To study enhanced CB1R signaling, we introduced a missense mutation (F238L) into the rat Cnr1 gene that encodes for the CB1R. According to our hypothesis, rats with the F238L mutation (Cnr1(F238L)) should sustain features of adolescent behavior into adulthood. Gain of function of the mutated receptor was demonstrated by in silico modeling and was verified functionally in a series of biochemical and electrophysiological experiments. Mutant rats exhibit an adolescent-like phenotype during adulthood compared with wild-type littermates, with typical high risk/novelty seeking, increased peer interaction, enhanced impulsivity, and augmented reward sensitivity for drug and nondrug reward. Partial inhibition of CB1R activity in Cnr1(F238L) mutant rats normalized behavior and led to a wild-type phenotype. We conclude that the activity state and functionality of the CB1R is critical for mediating adolescent behavior. These findings implicate the eCB system as an important research target for the neuropathology of adolescent-onset mental health disorders