Afferents Of Prefrontal Cortex Research Articles

Properties and modulation of excitatory inputs to the locus coeruleus.

Excitatory inputs drive burst firing of locus coeruleus (LC) noradrenaline (NA) neurons in response to a variety of stimuli. Though a small number of glutamatergic LC afferents have been investigated, the overall landscape of these excitatory inputs is largely unknown. The current study used an optogenetic approach to isolate three glutamatergic afferents: the prefrontal cortex (PFC), lateral hypothalamus (LH) and periaqueductal grey (PAG). AAV5-DIO-ChR2 was injected into each region in male and female CaMKII-Cre mice and the properties of excitatory inputs on LC-NA cells were measured. Notably we found differences among these inputs. First, the pattern of axonal innervation differed between inputs such that LH afferents were concentrated in the posterior portion of the LC-NA somatic region while PFC afferents were denser in the medial dendritic region. Second, basal intrinsic properties varied for afferents, with LH inputs having the highest connectivity and the largest amplitude excitatory postsynaptic currents while PAG inputs had the lowest initial release probability. Third, while orexin and oxytocin had minimal effects on any input, dynorphin strongly inhibited excitatory inputs originating from the LH and PAG, and corticotrophin releasing factor (CRF) selectively inhibited inputs from the PAG. Overall, these results demonstrate that individual afferents to the LC have differing properties, which may contribute to the modularity of the LC and its ability to mediate various behavioural outcomes. KEY POINTS: Excitatory inputs to the locus coeruleus (LC) are important for driving noradrenaline neuron activity and downstream behaviours in response to salient stimuli, but little is known about the functional properties of different glutamate inputs that innervate these neurons We used a virus-mediated optogenetic approach to compare glutamate afferents from the prefrontal cortex (PFC), the lateral hypothalamus (LH) and the periaqueductal grey (PAG). While PFC was predicted to make synaptic inputs, we found that the LH and PAG also drove robust excitatory events in LC noradrenaline neurons. The strength, kinetics, and short-term plasticity of each input differed as did the extent of neuromodulation by both dynorphin and corticotrophin releasing factor. Thus each input displayed a unique set of basal properties and modulation by peptides. This characterization is an important step in deciphering the heterogeneity of the LC.

Binge Alcohol Drinking Alters Synaptic Processing of Executive and Emotional Information in Core Nucleus Accumbens Medium Spiny Neurons.

The nucleus accumbens (NAc) is a forebrain region mediating the positive-reinforcing properties of drugs of abuse, including alcohol. It receives glutamatergic projections from multiple forebrain and limbic regions such as the prefrontal cortex (PFCx) and basolateral amygdala (BLA), respectively. However, it is unknown how NAc medium spiny neurons (MSNs) integrate PFCx and BLA inputs, and how this integration is affected by alcohol exposure. Because progress has been hampered by the inability to independently stimulate different pathways, we implemented a dual wavelength optogenetic approach to selectively and independently stimulate PFCx and BLA NAc inputs within the same brain slice. This approach functionally demonstrates that PFCx and BLA inputs synapse onto the same MSNs where they reciprocally inhibit each other pre-synaptically in a strict time-dependent manner. In alcohol-naïve mice, this temporal gating of BLA-inputs by PFCx afferents is stronger than the reverse, revealing that MSNs prioritize high-order executive processes information from the PFCx. Importantly, binge alcohol drinking alters this reciprocal inhibition by unilaterally strengthening BLA inhibition of PFCx inputs. In line with this observation, we demonstrate that in vivo optogenetic stimulation of the BLA, but not PFCx, blocks binge alcohol drinking escalation in mice. Overall, our results identify NAc MSNs as a key integrator of executive and emotional information and show that this integration is dysregulated during binge alcohol drinking.

Endocannabinoid Actions on Cortical Terminals Orchestrate Local Modulation of Dopamine Release in the Nucleus Accumbens

Dopamine (DA) transmission mediates numerous aspects of behavior. Although DA release is strongly linked to firing of DA neurons, recent developments indicate the importance of presynaptic modulation at striatal dopaminergic terminals. The endocannabinoid (eCB) system regulates DA release and is a canonical gatekeeper of goal-directed behavior. Here we report that extracellular DA increases induced by selective optogenetic activation of cholinergic neurons in the nucleus accumbens (NAc) are inhibited by CB1 agonists and eCBs. This modulation requires CB1 receptors on cortical glutamatergic afferents. Dopamine increases driven by optogenetic activation of prefrontal cortex (PFC) terminals in the NAc are similarly modulated by activation of these CB1 receptors. We further demonstrate that this same population of CB1 receptors modulates optical self-stimulation sustained by activation of PFC afferents in the NAc. These results establish local eCB actions on PFC terminals within the NAc that inhibit mesolimbic DA release and constrain reward-driven behavior.

Bilateral six-hydroxydopamine administration to PFC prevents the expression of behavioral sensitization to methylphenidate

Psychostimulants like amphetamine and methylphenidate (MPD) are used to treat attention deficit hyperactivity disorder (ADHD), which is marked by developmentally inappropriate inattention, hyperactivity, and impulsivity. Neuropsychological analyses indicate that ADHD patients are impaired on tasks of behavioral inhibition, reward reversal, and working memory, which are functions of the prefrontal cortex (PFC) and are modulated by the mesocortical dopamine (DA) system. Non-specific electrical lesioning of PFC eliminated the expression of behavioral sensitization elicited by chronic MPD administration. Behavioral sensitization is the progressive augmentation of locomotor activity as a result of repetitive (chronic) exposure to the drug. It is believed that the sensitization to chronic drug treatment is caused due to an increase in DA in the mesocorticolimbic DA system, which includes the PFC. Therefore, this study investigated the role of PFC DA in mediating the behavioral sensitization to repeated administration of MPD in adult male Sprague–Dawley rats. On experimental day (ED) 1, the behavior was recorded post-saline injection. On ED 2, the rats were divided into three groups—control, sham and bilateral 6-OHDA treated group; and the sham and 6-OHDA treated groups underwent respective surgeries. After 5 days of rest following surgery, the post-surgery baseline was recorded on ED 8 following a saline injection. All three groups received 2.5 mg/kg MPD for 6 days (from ED 9 to ED 14), followed by a 3-day washout period (ED 15 to ED 18). On ED 19, a rechallenge injection of 2.5 mg/kg MPD was given and locomotor activity was recorded. It was found that the 6-OHDA lesion group failed to exhibit behavioral sensitization to MPD. The involvement of the dopaminergic afferents of PFC in behavioral sensitization to MPD is discussed.

Projections from the Rat Prefrontal Cortex to the Ventral Tegmental Area: Target Specificity in the Synaptic Associations with Mesoaccumbens and Mesocortical Neurons

Excitatory projections from the prefrontal cortex (PFC) to the ventral tegmental area (VTA) play an important role in regulating the activity of VTA neurons and the extracellular levels of dopamine (DA) within forebrain regions. Previous investigations have demonstrated that PFC terminals synapse on the dendrites of DA and non-DA neurons in the VTA. However, the projection targets of these cells are not known. To address whether PFC afferents innervate different populations of VTA neurons that project to the nucleus accumbens (NAc) or to the PFC, a triple labeling method was used that combined peroxidase markers for anterograde and retrograde tract-tracing with pre-embedding immunogold-silver labeling for either tyrosine hydroxylase (TH) or GABA. Within the VTA, PFC terminals formed asymmetric synapses onto dendritic shafts that were immunoreactive for either TH or GABA. PFC terminals also synapsed on VTA dendrites that were retrogradely labeled from the NAc or the PFC. Dendrites retrogradely labeled from the NAc and postsynaptic to PFC afferents were sometimes immunoreactive for GABA but were never TH-labeled. Conversely, dendrites retrogradely labeled from the PFC and postsynaptic to PFC afferents were sometimes immunoreactive for TH but were never GABA-labeled. These results provide the first demonstration of PFC afferents synapsing on identified cell populations in the VTA and indicate a considerable degree of specificity in the targets of the PFC projection. The unexpected finding of selective PFC synaptic input to GABA-containing mesoaccumbens neurons and DA-containing mesocortical neurons suggests novel mechanisms through which the PFC can influence the activity of ascending DA and GABA projections.

Prefrontal cortical projections to the cholinergic neurons in the basal forebrain

The prefrontal cortex (PFC) projections to the basal forebrain cholinergic cell groups in the medial septum (MS), vertical and horizontal limbs of the diagonal band of Broca (VDB and HDB), and the magnocellular basal nucleus (MBN) in the rat were investigated by anterograde transport of Phaseolus vulgaris leuco-agglutinin (PHA-L) combined with acetylcholinesterase (AChE) histochemistry or choline acetyltransferase (ChAT) immunocytochemistry. The experiments revealed rich PHA-L-labeled projections to discrete parts of the basal forebrain cholinergic system (BFChS) essentially originating from all prefrontal areas investigated. The PFC afferents to the BFChS display a topographic organization, such that medial prefrontal areas project to the MS, VDB, and the medial part of the HDB, whereas the orbital and agranular insular areas predominantly innervate the HDB and MBN, respectively. Since the recurrent BFChS projection to the prefrontal cortex is arranged according to a similar topography, the relationship between the BFChS and the prefrontal cortex is characterized by reciprocal connections. Furthermore, tracer injections in the PFC resulted in anterograde labeling of numerous "en passant" and terminal boutons apposing perikarya and proximal dendrites of neurons in the basal forebrain, which were stained for the cholinergic marker enzymes. These results indicate that prefrontal cortical afferents make direct synaptic contacts upon the cholinergic neurons in the basal forebrain, although further analysis at the electron microscopic level will be needed to provide conclusive evidence.