Regulation of body weight and energy homeostasis by neuronal cell adhesion molecule 1

Susceptibility to obesity is linked to genes regulating neurotransmission, pancreatic beta-cell function and energy homeostasis. Genome-wide association studies have identified associations between body mass index and two loci near cell adhesion molecule 1 (CADM1) and cell adhesion molecule 2 (CADM2), which encode membrane proteins that mediate synaptic assembly. We found that these respective risk variants associate with increased CADM1 and CADM2 expression in the hypothalamus of human subjects. Expression of both genes was elevated in obese mice, and induction of Cadm1 in excitatory neurons facilitated weight gain while exacerbating energy expenditure. Loss of Cadm1 protected mice from obesity, and tract-tracing analysis revealed Cadm1-positive innervation of POMC neurons via afferent projections originating from beyond the arcuate nucleus. Reducing Cadm1 expression in the hypothalamus and hippocampus promoted a negative energy balance and weight loss. These data identify essential roles for Cadm1-mediated neuronal input in weight regulation and provide insight into the central pathways contributing to human obesity.</p

Optogenetische Untersuchung der dendritenspezifischen synaptischen Integration unter Einfluss der Netzwerkaktivität

Excitatory cortical pyramidal neurons are the principal output of the neocortex, and have been associated with advanced cognitive functions of the brain. Pyramidal neurons display an anatomical and functional segregation whereby the basal and apical dendrites, that extend to different cortical layers, receive synaptic inputs from different sources. This structure gives them the hypothesized ability to function as an associative link between different streams of information arriving to the cortex to electrotonically distant branches of single neurons. In vivo cortical pyramidal neurons are constantly active but it is unclear how network activity impacts on synaptic input integration. The aim of this study is to investigate whether synaptic integration in layer 2/3 pyramidal neurons in vivo is determined by input location, moreover I assess the contribution of cortical network activity to dendrite-specific integration. I used subcellular two-photon stimulation of Channelrhodopsin-2 expressing neurons and in vivo whole-cell recordings to show that network activity acts as a location specific modulator of synaptic input strength. Synaptic input to apical dendrites is reduced and compartmentalized in a distant-dependent manner during slow network activity in anesthetize and awake animals. However during active movement in awake mice input from apical dendrites is increased in amplitude. On the other hand, basal synaptic input undergoes a gain modulation during slow network activity whereby small amplitude inputs are amplified and large amplitude inputs are reduced. Activity-dependent gain modulation was also observed for glutamatergic thalamic and local monosynaptic pyramidal cell inputs thought to target basal dendrites. Basal dendritic gain modulation was dependent on a postsynaptic mechanism involving voltage-gated sodium channels. Thus, I propose that a central functional role of slow cortical network activity is to compartmentalize processing of top-down information thought to target apical dendrites, while amplifying small amplitude bottom-up inputs to basal dendrites. This cell-intrinsic mechanism could serve to bind functionally distinct subthreshold information in single cells.Erregende Pyramidalzellen stellen die primären Ausgänge des Neokortex dar, und werden mit höheren kognitiven Funktionen des Gehirns in Verbindung gebracht. Pyramidalzellen zeigen eine anatomische und funktionelle Aufteilung, bei der die apikalen und die basalen Dendriten, die sich in verschiedene kortikale Schichten erstrecken, synaptische Eingänge aus verschiedenen Quellen erhalten. Durch diesen Aufbau könnten sie als Verbindung zwischen verschiedenen Informationsströmen fungieren, die an elektrotonisch weit voneinander entfernten Verzweigungen einzelner Neurone im Kortex ankommen. Kortikale Pyramidalzellen sind in vivo kontinuierlich aktiv, aber es ist unklar, wie die Netzwerkaktivität die Integration synaptischer Eingänge beeinflusst. Das Ziel dieser Studie ist es, zu untersuchen, ob die synaptische Integration in Pyramidalzellen in Schicht 2/3 in vivo durch den Ort des Informationseingangs bestimmt wird. Des Weiteren betrachte ich den Beitrag kortikaler Netzwerkaktivität zur Dendriten-spezifischen Integration. Ich habe subzelluläre Zwei-Photonen-Stimulation von Channelrhodopsin-2-exprimierenden Neuronen sowie in vivo Ganzzellableitungen verwendet, um zu zeigen, dass die Netzwerkaktivität als ortsspezifischer Modulator der synaptischen Eingangsstärke wirkt. Synaptische Eingänge an apikalen Dendriten sind während langsamer Netzwerkaktivität in narkotisierten und wachen Tieren in einer entfernungsabhängigen Weise abgeschwächt und in Abschnitte gegliedert. Während aktiver Bewegungen wacher Mäuse zeigen die Eingänge von apikalen Dendriten jedoch eine größere Amplitude. Synaptische Eingänge basaler Dendriten wiederum zeigen eine Modulation des Verstärkungsfaktors während langsamer Netzwerkaktivität, durch die Eingänge kleiner Amplitude verstärkt und großer Amplitude abgeschwächt werden. Eine aktivitätsabhängige Modulation der Verstärkung wurde auch bei glutamatergen Eingängen vom Thalamus sowie lokalen monosynaptischen Pyramidalzelleingängen beobachtet, die vermutlich an basalen Dendriten ansetzen. Die Modulation der Verstärkung an basalen Dendriten hing von einem postsynaptischen Mechanismus unter Mitwirkung spannungsabhängiger Natriumkanäle ab. Somit ist es meine Hypothese, dass es eine zentrale funktionelle Rolle langsamer Netzwerkaktivität ist, die Verarbeitung vermutlich an apikalen Dendriten eintreffender Top-Down-Information aufzugliedern, während Bottom-Up-Eingänge kleiner Amplitude an basalen Dendriten verstärkt werden. Dieser den Zellen intrinsische Mechanismus könnte dazu dienen, funktionell unterschiedliche unterschwellige Informationen in einzelnen Zellen zu verbinden

Dendrite-Specific Amplification of Weak Synaptic Input during Network Activity In Vivo

Summary: Excitatory synaptic input reaches the soma of a cortical excitatory pyramidal neuron via anatomically segregated apical and basal dendrites. In vivo, dendritic inputs are integrated during depolarized network activity, but how network activity affects apical and basal inputs is not understood. Using subcellular two-photon stimulation of Channelrhodopsin2-expressing layer 2/3 pyramidal neurons in somatosensory cortex, nucleus-specific thalamic optogenetic stimulation, and paired recordings, we show that slow, depolarized network activity amplifies small-amplitude synaptic inputs targeted to basal dendrites but reduces the amplitude of all inputs from apical dendrites and the cell soma. Intracellular pharmacology and mathematical modeling suggests that the amplification of weak basal inputs is mediated by postsynaptic voltage-gated channels. Thus, network activity dynamically reconfigures the relative somatic contribution of apical and basal inputs and could act to enhance the detectability of weak synaptic inputs. : Ferrarese et al. investigate the impact of network activity on synaptic integration in cortical L2/3 pyramidal neurons in vivo. They report a reduction of apical dendritic inputs but an amplification of small-amplitude basal inputs during depolarized phases of slow network activity. The amplification is dependent on postsynaptic voltage-gated channels

Article Aversion to Nicotine Is Regulated by the Balanced Activity of b4 and a5 Nicotinic Receptor Subunits in the Medial Habenula

International audienceNicotine dependence is linked to single nucleotide polymorphisms in the CHRNB4-CHRNA3-CHRNA5 gene cluster encoding the a3b4a5 nicotinic acetyl-choline receptor (nAChR). Here we show that the b4 subunit is rate limiting for receptor activity, and that current increase by b4 is maximally competed by one of the most frequent variants associated with tobacco usage (D398N in a5). We identify a b4-specific residue (S435), mapping to the intracellular vestibule of the a3b4a5 receptor in close proximity to a5 D398N, that is essential for its ability to increase currents. Transgenic mice with targeted overexpres-sion of Chrnb4 to endogenous sites display a strong aversion to nicotine that can be reversed by viral-mediated expression of the a5 D398N variant in the medial habenula (MHb). Thus, this study both provides insights into a3b4a5 receptor-mediated mechanisms contributing to nicotine consumption, and identifies the MHb as a critical element in the circuitry controlling nicotine-dependent phenotypes

Regulation of body weight and energy homeostasis by neuronal cell adhesion molecule 1

Susceptibility to obesity is linked to genes regulating neurotransmission, pancreatic beta-cell function and energy homeostasis. Genome-wide association studies have identified associations between body mass index and two loci near cell adhesion molecule 1 (CADM1) and cell adhesion molecule 2 (CADM2), which encode membrane proteins that mediate synaptic assembly. We found that these respective risk variants associate with increased CADM1 and CADM2 expression in the hypothalamus of human subjects. Expression of both genes was elevated in obese mice, and induction of Cadm1 in excitatory neurons facilitated weight gain while exacerbating energy expenditure. Loss of Cadm1 protected mice from obesity, and tract-tracing analysis revealed Cadm1-positive innervation of POMC neurons via afferent projections originating from beyond the arcuate nucleus. Reducing Cadm1 expression in the hypothalamus and hippocampus promoted a negative energy balance and weight loss. These data identify essential roles for Cadm1-mediated neuronal input in weight regulation and provide insight into the central pathways contributing to human obesit