The medial prefrontal cortex (mPFC) steers goal-directed actions and withholds inappropriate behavior. Dorsal and ventral mPFC (dmPFC/vmPFC) circuits have distinct roles in cognitive control, but ...underlying mechanisms are poorly understood. Here we use neuroanatomical tracing techniques, in vitro electrophysiology, chemogenetics and fiber photometry in rats engaged in a 5-choice serial reaction time task to characterize dmPFC and vmPFC outputs to distinct thalamic and striatal subdomains. We identify four spatially segregated projection neuron populations in the mPFC. Using fiber photometry we show that these projections distinctly encode behavior. Postsynaptic striatal and thalamic neurons differentially process synaptic inputs from dmPFC and vmPFC, highlighting mechanisms that potentially amplify distinct pathways underlying cognitive control of behavior. Chemogenetic silencing of dmPFC and vmPFC projections to lateral and medial mediodorsal thalamus subregions oppositely regulate cognitive control. In addition, dmPFC neurons projecting to striatum and thalamus divergently regulate cognitive control. Collectively, we show that mPFC output pathways targeting anatomically and functionally distinct striatal and thalamic subregions encode bi-directional command of cognitive control.
Neocortical choline acetyltransferase (ChAT)-expressing interneurons are a subclass of vasoactive intestinal peptide (ChAT-VIP) neurons of which circuit and behavioural function are unknown. Here, we ...show that ChAT-VIP neurons directly excite neighbouring neurons in several layers through fast synaptic transmission of acetylcholine (ACh) in rodent medial prefrontal cortex (mPFC). Both interneurons in layers (L)1-3 as well as pyramidal neurons in L2/3 and L6 receive direct inputs from ChAT-VIP neurons mediated by fast cholinergic transmission. A fraction (10-20%) of postsynaptic neurons that received cholinergic input from ChAT-VIP interneurons also received GABAergic input from these neurons. In contrast to regular VIP interneurons, ChAT-VIP neurons did not disinhibit pyramidal neurons. Finally, we show that activity of these neurons is relevant for behaviour and they control attention behaviour distinctly from basal forebrain ACh inputs. Thus, ChAT-VIP neurons are a local source of cortical ACh that directly excite neurons throughout cortical layers and contribute to attention.
Which of the two theories better depicts the very first pathological changes in MS is debated. Since a better evaluation of MS etiopathogenesis could also optimize patients' management, the present ...issue was aimed to stimulate a discussion about possible overlooked candidates in support of each theory. ...dysregulation of immune responses, promoted by the genetic background and potentially triggered by environmental factors, could represent the main mechanism in MS onset and progression. Cennamo et al. applied Optical Coherence Tomography to investigate the role of peripapillary vessel density as an early biomarker in MS. This tool was relevant for identifying patients in the earliest phases of MS. Todea et al. showed how magnetic resonance imaging (MRI) enables identification of focal demyelination in white matter and cortical lesions already from the earliest phases of MS. Lesion burden was associated with serum neurofilament light chain (sNfL) levels, a biomarker of axonal injury. ...the 2-year longitudinal changes of cortical and white matter lesion burden correlated with the cognitive performances of MS patients.
Acetylcholine (ACh) signaling shapes neuronal circuit development and underlies specific aspects of cognitive functions and behaviors, including attention, learning, memory and motivation. During ...behavior, activation of muscarinic and nicotinic acetylcholine receptors (mAChRs and nAChRs) by ACh alters the activation state of neurons, and neuronal circuits most likely process information differently with elevated levels of ACh. In several brain regions, ACh has been shown to alter synaptic strength as well. By changing the rules for synaptic plasticity, ACh can have prolonged effects on and rearrange connectivity between neurons that outlasts its presence. From recent discoveries in the mouse, rat, monkey and human brain, a picture emerges in which the basal forebrain (BF) cholinergic system targets the neocortex with much more spatial and temporal detail than previously considered. Fast cholinergic synapses acting on a millisecond time scale are abundant in the mammalian cerebral cortex, and provide BF cholinergic neurons with the possibility to rapidly alter information flow in cortical microcircuits. Finally, recent studies have outlined novel mechanisms of how cholinergic projections from the BF affect synaptic strength in several brain areas of the rodent brain, with behavioral consequences. This review highlights these exciting developments and discusses how these findings translate to human brain circuitries.
Multiple Sclerosis (MS) is a complex and chronic disease of the central nervous system (CNS), characterized by both degenerative and inflammatory processes leading to axonal damage, demyelination, ...and neuronal loss. In the last decade, the traditional
standpoint on MS pathogenesis, which identifies a primary autoimmune inflammatory etiology, has been challenged by a complementary
theory. By focusing on the degenerative processes of MS, the axo-myelinic system may reveal new insights into the disease triggering mechanisms. Oxidative stress (OS) has been widely described as one of the means driving tissue injury in neurodegenerative disorders, including MS. Axonal mitochondria constitute the main energy source for electrically active axons and neurons and are largely vulnerable to oxidative injury. Consequently, axonal mitochondrial dysfunction might impair efficient axo-glial communication, which could, in turn, affect axonal integrity and the maintenance of axonal, neuronal, and synaptic signaling. In this review article, we argue that OS-derived mitochondrial impairment may underline the dysfunctional relationship between axons and their supportive glia cells, specifically oligodendrocytes and that this mechanism is implicated in the development of a primary cytodegeneration and a secondary pro-inflammatory response (
), which in turn, together with a variably primed host's immune system, may lead to the onset of MS and its different subtypes.
Nicotine stimulates the activity of mesolimbic dopamine neurons, which is believed to mediate the rewarding and addictive properties of tobacco use. Accumulating evidence suggests that the ...endocannabinoid system might play a major role in neuronal mechanisms underlying the rewarding properties of drugs of abuse, including nicotine. Here, we investigated the modulation of nicotine effects by the endocannabinoid system on dopamine neurons in the ventral tegmental area with electrophysiological techniques in vivo and in vitro. We discovered that pharmacological inhibition of fatty acid amide hydrolase (FAAH), the enzyme that catabolizes fatty acid ethanolamides, among which the endocannabinoid anandamide (AEA) is the best known, suppressed nicotine-induced excitation of dopamine cells. Importantly, this effect was mimicked by the administration of the FAAH substrates oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), but not methanandamide, the hydrolysis resistant analog of AEA. OEA and PEA are naturally occurring lipid signaling molecules structurally related to AEA, but devoid of affinity for cannabinoid receptors. They blocked the effects of nicotine by activation of the peroxisome proliferator-activated receptor-alpha (PPAR-alpha), a nuclear receptor transcription factor involved in several aspects of lipid metabolism and energy balance. Activation of PPAR-alpha triggered a nongenomic stimulation of tyrosine kinases, which might lead to phosphorylation and negative regulation of neuronal nicotinic acetylcholine receptors. These data indicate for the first time that the anorexic lipids OEA and PEA possess neuromodulatory properties as endogenous ligands of PPAR-alpha in the brain and provide a potential new target for the treatment of nicotine addiction.
Background:
In utero exposure to maternal viral infections is associated with a higher incidence of psychiatric disorders with a supposed neurodevelopmental origin, including schizophrenia. Hence, ...immune response factors exert a negative impact on brain maturation that predisposes the offspring to the emergence of pathological phenotypes later in life. Although ventral tegmental area dopamine neurons and their target regions play essential roles in the pathophysiology of psychoses, it remains to be fully elucidated how dopamine activity and functionality are disrupted in maternal immune activation models of schizophrenia.
Methods:
Here, we used an immune-mediated neurodevelopmental disruption model based on prenatal administration of the polyriboinosinic-polyribocytidilic acid in rats, which mimics a viral infection and recapitulates behavioral abnormalities relevant to psychiatric disorders in the offspring. Extracellular dopamine levels were measured by brain microdialysis in both the nucleus accumbens shell and the medial prefrontal cortex, whereas dopamine neurons in ventral tegmental area were studied by in vivo electrophysiology.
Results:
Polyriboinosinic-polyribocytidilic acid-treated animals, at adulthood, displayed deficits in sensorimotor gating, memory, and social interaction and increased baseline extracellular dopamine levels in the nucleus accumbens, but not in the prefrontal cortex. In polyriboinosinic-polyribocytidilic acid rats, dopamine neurons showed reduced spontaneously firing rate and population activity.
Conclusions:
These results confirm that maternal immune activation severely impairs dopamine system and that the polyriboinosinic-polyribocytidilic acid model can be considered a proper animal model of a psychiatric condition that fulfills a multidimensional set of validity criteria predictive of a human pathology.
•BDA tracing combined with neurochemical fingerprinting.•PV-cre mice and ChAT-cre mice.•AAV virus with eYFP construct to force neurochemically specific neurons to express fluorescent protein.•This ...virus as an agent to “switch on the light in cells” and reveal fibers.•Location of neurotransmission-related substance in nerve fibers in the CNS transgenic mice expressing GFP in small populations of neurochemically specific neurons.•Outlook for 4th generation neuroanatomical tracing techniques.
The first three generations of neuroanatomical tract-tracing methods include, respectively, techniques exploiting degeneration, retrograde cellular transport and anterograde cellular transport. This paper reviews the most recent development in third-generation tracing, i.e., neurochemical fingerprinting based on BDA tracing, and continues with an emerging tracing technique called here ‘selective fluorescent protein expression’ that in our view belongs to an entirely new ‘fourth-generation’ class. Tracing techniques in this class lean on gene expression technology designed to ‘label’ projections exclusively originating from neurons expressing a very specific molecular phenotype. Genetically engineered mice that express cre-recombinase in a neurochemically specific neuronal population receive into a brain locus of interest an injection of an adeno-associated virus (AAV) carrying a double-floxed promoter-eYFP DNA sequence. After transfection this sequence is expressed only in neurons metabolizing recombinase protein. These particular neurons promptly start manufacturing the fluorescent protein which then accumulates and labels to full detail all the neuronal processes, including fibers and terminal arborizations. All other neurons remain optically ‘dark’. The AAV is not replicated by the neurons, prohibiting intracerebral spread of ‘infection’. The essence is that the fiber projections of discrete subpopulations of neurochemically specific neurons can be traced in full detail. One condition is that the transgenic mouse strain is recombinase-perfect.
We illustrate selective fluorescent protein expression in parvalbumin-cre (PV-cre) mice and choline acetyltransferase-cre (ChAT-cre) mice. In addition we compare this novel tracing technique with observations in brains of native PV mice and ChAT-GFP mice. We include a note on tracing techniques using viruses.
Background Recent findings indicate that inhibitors of fatty acid amide hydrolase (FAAH) counteract the rewarding effects of nicotine in rats. Inhibition of FAAH increases levels of several ...endogenous substances in the brain, including the endocannabinoid anandamide and the noncannabinoid fatty acid ethanolamides oleoylethanolamide (OEA) and palmitoylethanolamide, which are ligands for alpha-type peroxisome proliferator-activated nuclear receptors (PPAR-α). Here, we evaluated whether directly acting PPAR-α agonists can modulate reward-related effects of nicotine. Methods We combined behavioral, neurochemical, and electrophysiological approaches to evaluate effects of the PPAR-α agonists 4-Chloro-6-(2,3-dimethylphenyl)amino-2-pyrimidinylthioacetic acid (WY14643) and methyl oleoylethanolamide (methOEA; a long-lasting form of OEA) on 1) nicotine self-administration in rats and squirrel monkeys; 2) reinstatement of nicotine-seeking behavior in rats and monkeys; 3) nicotine discrimination in rats; 4) nicotine-induced electrophysiological activity of ventral tegmental area dopamine neurons in anesthetized rats; and 5) nicotine-induced elevation of dopamine levels in the nucleus accumbens shell of freely moving rats. Results The PPAR-α agonists dose-dependently decreased nicotine self-administration and nicotine-induced reinstatement in rats and monkeys but did not alter food- or cocaine-reinforced operant behavior or the interoceptive effects of nicotine. The PPAR-α agonists also dose-dependently decreased nicotine-induced excitation of dopamine neurons in the ventral tegmental area and nicotine-induced elevations of dopamine levels in the nucleus accumbens shell of rats. The ability of WY14643 and methOEA to counteract the behavioral, electrophysiological, and neurochemical effects of nicotine was reversed by the PPAR-α antagonist 1-(4-Chlorophenyl)methyl-3-(1,1-dimethylethyl)thio-a,a-dimethyl-5-(1-methylethyl)-1H-Indole-2-propanoic acid (MK886). Conclusions These findings indicate that PPAR-α might provide a valuable new target for antismoking medications.
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